NOVEL HETEROARYL-TRIAZOLE COMPOUNDS AS PESTICIDES

Abstract

The present invention relates to novel heteroaryl-triazole compounds of the general formula (I), in which the structural elements X, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the meaning given in the description, to formulations and compositions comprising such compounds and for their use in the control of animal pests including arthropods and insects in plant protection and to their use for control of ectoparasites on animals.

##STR00001##

Claims

1. A compound of formula (I) ##STR00396## in which X is O or S; R.sup.1 is hydrogen; R.sup.2 is selected from the following substructure(s) Q1, in which the bond to the C═X— group is marked with a #: ##STR00397## or R.sup.2 is 2-chloro-6-(trifluoromethyl)pyridin-4-yl, 5-(trifluoromethyl)pyridin-3-yl, 5-(trifluoromethoxy)pyridin-3-yl, 6-chloro-4-(trifluoromethyl)pyridin-2-yl or 4,6-dichloropyridin-2-yl; R.sup.21 is halogen, —CN, —SF.sub.5, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3haloalkylthio, C.sub.1-C.sub.3haloalkylsulfinyl, C.sub.1-C.sub.3haloalkylsulfonyl, C.sub.1-C.sub.3alkylthio, C.sub.1-C.sub.3alkylsulfinyl, C.sub.1-C.sub.3alkylsulfonyl, difluoromethylsulfanyl, C.sub.3-C.sub.4cycloalkylthio, C.sub.3-C.sub.4cycloalkylsulfinyl, C.sub.3-C.sub.4cycloalkylsulfonyl, or phenylsulfonyl, wherein the phenyl is optionally substituted with one to two substituent(s) selected from the group of halogen, —CN, methyl, methoxy, trifluoromethyl or trifluoromethoxy; or cyclopropyl wherein the cyclopropyl is optionally substituted with one to two substituent(s) selected from the group of halogen, —CN, methyl, difluoromethyl or trifluoromethyl; R.sup.22 is halogen, —CN, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3haloalkylthio, C.sub.1-C.sub.3haloalkylsulfinyl, C.sub.1-C.sub.3haloalkylsulfonyl, C.sub.1-C.sub.3alkylthio, C.sub.1-C.sub.3alkylsulfinyl, C.sub.1-C.sub.3alkylsulfonyl, C.sub.3-C.sub.4cycloalkylthio, C.sub.3-C.sub.4cycloalkylsulfinyl, C.sub.3-C.sub.4cycloalkylsulfonyl; or cyclopropyl wherein the cyclopropyl is optionally substituted with one to two substituent(s) selected from the group of halogen, —CN, methyl, difluoromethyl or trifluoromethyl; R.sup.3 is hydrogen; R.sup.4 is —CN or a substituent selected from the following substructures S1-S2, in which the bond to the thiazole is marked with a #: ##STR00398## R.sup.41 is hydrogen, C.sub.1-C.sub.3alkyl or C.sub.1-C.sub.3haloalkyl; R.sup.42 is hydrogen, C.sub.3-C.sub.6cycloalkyl or C.sub.1-C.sub.6alkyl, wherein the C.sub.3-C.sub.6cycloalkyl or C.sub.1-C.sub.6alkyl is optionally substituted with one to three halogen atoms and/or is optionally substituted with one substituent selected from the group of —CN, methoxy, trifluoromethyl, methylsulfonyl and cyclopropyl; R.sup.5 is hydrogen, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkoxy or C.sub.3-C.sub.6cycloalkyl.

2. The compound according to claim 1, in which X is O or S; R.sup.1 is hydrogen; R.sup.2 is selected from the following substructure(s) Q1, in which the bond to the C═X— group is marked with a #: ##STR00399## or R.sup.2 is 2-chloro-6-(trifluoromethyl)pyridin-4-yl, 5-(trifluoromethyl)pyridin-3-yl, 5-(trifluoromethoxy)pyridin-3-yl, 6-chloro-4-(trifluoromethyl)pyridin-2-yl, or 4,6-dichloropyridin-2-yl; R.sup.21 is chlorine, fluorine, bromine, iodine, —CN, —SF.sub.5, difluoromethyl, chloro(difluoro)methyl, bromo(difluoro)methyl, trifluoromethyl, 1,1-difluoroethyl, 2-fluoropropanyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, difluoromethylsulfanyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, (4-chlorophenyl)sulfonyl, cyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclopropyl or 1-cyanocyclopropyl; R.sup.22 is chlorine, fluorine, bromine, iodine, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, difluoromethoxy, trifluoromethoxy, difluoromethylsulfonyl, trifluoromethylsulfonyl; R.sup.3 is hydrogen; R.sup.4 is —CN or a substituent selected from the following substructures S1-S2, in which the bond to the thiazole is marked with a #: ##STR00400## R.sup.41 is hydrogen or methyl; R.sup.42 is hydrogen, cyclopropyl or C.sub.1-C.sub.3alkyl, wherein the C.sub.1-C.sub.3alkyl is optionally substituted with one substituent selected from the group of —CN, methoxy, trifluoromethyl, isopropyl and cyclopropyl; R.sup.5 is hydrogen, methyl, methoxy or cyclopropyl.

3. The compound according to claim 1, in which X is O; R.sup.1 is hydrogen; R.sup.2 is 3-chloro-5-(trifluoromethylsulfonyl)phenyl, 3-chloro-5-(difluoromethylsulfonyl)phenyl, 3-chloro-5-cyclopropylphenyl, 3-(difluoromethoxy)-5-(difluoromethylthio)phenyl, 3-fluoro-5-(trifluoromethoxy)phenyl, 3-cyano-5-(trifluoromethoxy)phenyl, 3-(difluoromethoxy)-5-(difluoromethylsulfonyl)phenyl, 3,5-bis(trifluoromethylsulfonyl)phenyl, 2-chloro-6-(trifluoromethoxy)pyridin-4-yl, 3-chloro-5-(4-chlorophenyl)sulfonylphenyl, 3,5-bis(trifluoromethoxy)phenyl, 3-(difluoromethylsulfonyl)-5-(trifluoromethoxy)phenyl, 6-chloro-4-(trifluoromethyl)pyridin-2-yl, 4,6-dichloropyridin-2-yl, 5-(trifluoromethoxy)pyridin-3-yl, 3-chloro-5-(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 3-bromo-5-chlorophenyl, 3,5-dibromophenyl, 3-bromo-5-(trifluoromethyl)phenyl, 3-bromo-5-cyanophenyl, 3-cyano-5-(trifluoromethyl)phenyl, 3-bromo-5-(trifluoromethoxy)phenyl, 3-chloro-5-(difluoromethyl)phenyl, 3-chloro-5-(1,1,2,2,2-pentafluoroethyl)phenyl, 2-chloro-6-(trifluoromethyl)pyridin-4-yl, 3-cyclopropyl-5-(trifluoromethoxy)phenyl, 3-(difluoromethyl)-5-(trifluoromethoxy)phenyl, 3-chloro-5-(trifluoromethoxy)phenyl, 3-bromo-5-iodophenyl, 3,5-bis(difluoromethoxy)phenyl, 3-chloro-5-(pentafluoro-lambda.sup.6-sulfanyl)phenyl, 3,5-bis(difluoromethyl)phenyl, 3-(difluoromethoxy)-5-(difluoromethyl)phenyl, 3-cyclopropyl-5-(difluoromethoxy)phenyl, 3-chloro-5-(methylsulfonyl)phenyl, 3-methylsulfonyl-5-(trifluoromethoxy)phenyl, 3-(difluoromethoxy)-5-iodophenyl, 3-bromo-5-(difluoromethoxy)phenyl, 3-cyano-5-fluorophenyl, 3-chloro-5-cyclopropylsulfonylphenyl, 3-bromo-5-(1-fluorocyclopropyl)phenyl, 3-cyclopropyl-5-(difluoromethyl)phenyl, 3-bromo-5-(2,2-difluorocyclopropyl)phenyl, 3-bromo-5-(1,1-difluoroethyl)phenyl, 3-(difluoromethyl)-5-fluorophenyl, 3-cyclopropylsulfonyl-5-(difluoromethoxy)phenyl, 3-chloro-5-[(trifluoromethyl)sulfonyl]phenyl, 3-cyclopropylsulfonyl-5-(difluoromethyl)phenyl, 3-chloro-5-(1-cyanocyclopropyl)phenyl, 3-(difluoromethoxy)-5-fluorophenyl, 3-(difluoromethoxy)-5-methylsulfonylphenyl, 3-bromo-5-[(trifluoromethyl)sulfonyl]phenyl, 3-(isopropylsulfonyl)-5-(trifluoromethoxy)phenyl, 3-(ethylsulfonyl)-5-(trifluoromethoxy)phenyl, 3-(cyclopropylsulfonyl)-5-(trifluoromethoxy)phenyl, 3-(methylsulfonyl)-5-(trifluoromethyl)phenyl, 3-cyclopropyl-5-[(trifluoromethyl)sulfonyl]phenyl, 5-(trifluoromethyl)pyridin-3-yl, 3-chloro-5-iodophenyl, 3-chloro-5-[chloro(difluoro)methyl]phenyl, 3-[bromo(difluoro)methyl]-5-chlorophenyl, 3-(1-cyanocyclopropyl)-5-(trifluoromethoxy)phenyl, 3-bromo-5-(2,2,2-trifluoroethoxy)phenyl, 3-cyclopropyl-5-(1,1-difluoroethyl)phenyl, 3-bromo-5-(2-fluoropropan-2-yl)phenyl, 3-(difluoromethoxy)-5-(trifluoromethoxy)phenyl, or 3-chloro-5-cyanophenyl; R.sup.3 is hydrogen; R.sup.4 is —CN, [2-methoxyethyl(methyl)amino]carbonyl, [cyclopropylmethyl(methyl)amino]carbonyl, dimethylaminocarbonyl, [ethyl(methyl)amino]carbonyl, [cyclopropyl(methyl)amino]carbonyl, [methyl(2-methylpropyl)amino]carbonyl, [cyanomethyl(methyl)amino]carbonyl, [isopropyl(methyl)amino]carbonyl, [methyl(2,2,2-trifluoroethyl)amino]carbonyl, aminocarbonyl, (cyclopropylamino)carbonyl, (isopropylamino)carbonyl, or (methylamino)carbonyl; R.sup.5 is hydrogen, methyl, methoxy or cyclopropyl.

4. The compound according to claim 1, comprising a structure according to formula (I′) ##STR00401##

5. A compound of formula (1) ##STR00402## and/or a salt thereof in which R.sup.1 is hydrogen; R.sup.3 is hydrogen; R.sup.4 is —CN or a substituent selected from the following substructures S1-S2, in which the bond to the thiazole is marked with a #: ##STR00403## R.sup.5 is hydrogen, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkoxy or C.sub.3-C.sub.6cycloalkyl.

6. The compound according to claim 5, in which R.sup.4 is —CO.sub.2—C.sub.1-C.sub.6alkyl.

7. A compound of formula (11a): ##STR00404## and/or a salt thereof in which R.sup.1 is hydrogen; R.sup.2 is selected from the following substructure(s) Q1, in which the bond to the C═X— group is marked with a #: ##STR00405## R.sup.5 is hydrogen, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkoxy or C.sub.3-C.sub.6cycloalkyl, and Alkyl is C1-C6alkyl.

8. A compound of formula (12a): ##STR00406## and/or a salt thereof in which R.sup.1 is hydrogen; R.sup.2 is selected from the following substructure(s) Q1, in which the bond to the C═X— group is marked with a #: ##STR00407## R.sup.5 is hydrogen, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkoxy or C.sub.3-C.sub.6cycloalkyl.

9. One or more compounds selected from the group consisting of 2-[5-(1-aminoethyl)-1H-1,2,4-triazol-1-yl]-1,3-thiazole-5-carbonitrile, 2-{5-[(1S)-1-aminoethyl]-3-methyl-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carbonitrile, 2-{5-[(1S)-1-aminoethyl]-3-methyl-1H-1,2,4-triazol-1-yl}-N-(cyanomethyl)-N-methyl-1,3-thiazole-5-carboxamide, 2-{5-[(1S)-1-aminoethyl]-3-methyl-1H-1,2,4-triazol-1-yl}-N,N-dimethyl-,3-thiazole-5-carboxamide, methyl 2-{5-[(1S)-1-aminoethyl]-3-methyl-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carboxylate, 3-(methylsulfonyl)-5-(trifluoromethoxy)benzoic acid, 2-{5-[(1S)-1-aminoethyl]-3-cyclopropyl-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carbonitrile, 3-(difluoromethyl)-5-(methylsulfonyl)benzoic acid, 3-(difluoromethoxy)-5-(methylsulfonyl)benzoic acid, 3-bromo-5-(1-fluorocyclopropyl)benzoic acid, 3-bromo-5-(1,1-difluoroethyl)benzoic acid, 3-bromo-5-(2,2-difluorocyclopropyl)benzoic acid, 3-cyclopropyl-5-[(trifluoromethyl)sulfonyl]benzoic acid, 3-(cyclopropylsulfonyl)-5-(difluoromethoxy)benzoic acid, 3-(cyclopropylsulfonyl)-5-(difluoromethyl)benzoic acid, 3-(cyclopropylsulfonyl)-5-(trifluoromethoxy)benzoic acid, 3-(ethylsulfonyl)-5-(trifluoromethoxy)benzoic acid, 3-(isopropylsulfonyl)-5-(trifluoromethoxy)benzoic acid, 2-{5-[(1S)-1-aminoethyl]-1H-1,2,4-triazol-1-yl}-N,N-dimethyl-1,3-thiazole-5-carboxamide, 2-[5-[(1S)-1-aminoethyl]-1,2,4-triazol-1-yl]-N-methyl-thiazole-5-carboxamide, 3-(1-cyanocyclopropyl)-5-(trifluoromethoxy)benzoic acid, 3-chloro-5-(bromodifluoromethyl)benzoic acid, 3-chloro-5-(chlorodifluoromethyl)benzoic acid, 3-bromo-5-(2-fluoropropan-2-yl)benzoic acid, 3-(difluoromethoxy)-5-(trifluoromethoxy)benzoic acid, 3-cyclopropyl-5-(1,1-difluoroethyl)benzoic acid, methyl 2-[5-[(1S)-1-[[3,5-bis(trifluoromethyl)benzoyl]amino]ethyl]-3-methyl-1,2,4-triazol-1-yl]thiazole-5-carboxylate, methyl 2-[5-[(1S)-1-[[3-chloro-5-(trifluoromethyl)benzoyl]amino]ethyl]-3-methyl-1,2,4-triazol-1-yl]thiazole-5-carboxylate, 2-[5-[(1S)-1-[[3,5-bis(trifluoromethyl)benzoyl]amino]ethyl]-3-methyl-1,2,4-triazol-1-yl]thiazole-5-carboxylic acid, 2-[5-[(1S)-1-[[3-chloro-5-(trifluoromethyl)benzoyl]amino]ethyl]-3-methyl-1,2,4-triazol-1-yl]thiazole-5-carboxylic acid, 2-{5-[(1S)-1-aminoethyl]-1H-1,2,4-triazol-1-yl}-N-cyclopropyl-N-methyl-1,3-thiazole-5-carboxamide, methyl 2-{5-[(1S)-1-aminoethyl]-3-cyclopropyl-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carboxylate, 3-(difluoromethoxy)-5-[(difluoromethyl)sulfanyl]benzoic acid, methyl 2-(3-cyclopropyl-5-{(1S)-1-1-[3-cyclopropyl-5-(trifluoromethoxy)benzamido]ethyl}-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxylate, 2-(3-cyclopropyl-5-{(1S)-1-[3-cyclopropyl-5-(trifluoromethoxy)benzamido]ethyl}-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxylic acid, 2-(3-cyclopropyl-5-{(1S)-1-[3-(methylsulfonyl)-5-(trifluoromethoxy)benzamido]ethyl}-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxylic acid, 2-[5-(1-aminoethyl)-3-methoxy-1H-1,2,4-triazol-1-yl]-1,3-thiazole-5-carbonitrile, 2-[5-[(1S)-1-aminoethyl]-3-cyclopropyl-1,2,4-triazol-1-yl]-N,N-dimethyl-thiazole-5-carboxamide, and salts thereof.

10. A formulation, optionally an agrochemical formulation, comprising at least one compound of formula (I) according to claim 1.

11. The formulation according to claim 10, further comprising at least one extender and/or at least one surface-active substance.

12. The formulation according to claim 10, wherein the compound of formula (I) is in a mixture with at least one further active compound.

13. A method for controlling one or more pests, optionally animal pests, comprising allowing a compound of formula (I) according to claim 1 or a formulation thereof to act on the pests and/or a habitat thereof.

14. The method according to claim 13, wherein the pest is an animal pest and comprises an insect, an arachnid or a nematode, or the pest is an insect or an arachnid.

15. A product comprising a compound of formula (I) according to claim 1 or a formulation thereof for controlling one or more animal pests.

16. The product according to claim 15, wherein the animal pest comprises an insect or an arachnid, or the animal pest is an insect or an arachnid.

17. The product according to claim 15 in crop protection.

18. The product according to claim 15 in the field of animal health.

19. A method for protecting seed and/or a germinating plant from one or more pests, optionally animal pests, comprising contacting the seed with a compound of formula (I) according to claim 1 or a formulation thereof.

20. The seed obtained by a method according to claim 19.

Description

PREPARATION OF EXAMPLES

Synthesis of methyl 2-hydrazino-1,3-thiazole-5-carboxylate

[0518] ##STR00036##

[0519] A mixture of 5.0 g (28.1 mmol) methyl 2-chloro-1,3-thiazole-5-carboxylate and 56.3 ml (56.3 mmol) of a 1M solution of hydrazine in THF was refluxed for 2.5 h. After cooling to room temperature, the mixture was evaporated and then the residue was suspended in 50 ml hot water. The resulting precipitate was filtered, washed with water and dried under vacuo to yield the title compound (4.3 g).

[0520] .sup.1H NMR peak list (400 MHz, d6-DMSO): δ=9.4620 (1.6); 7.7535 (5.8); 5.1545 (4.2); 3.7122 (16.0); 3.3350 (8.0); 2.5255 (0.4); 2.5117 (8.7); 2.5075 (17.1); 2.5030 (22.3); 2.4985 (16.8); 2.4943 (8.6)

[0521] ESI mass [m/z]: 174.0 [M+H].sup.+

Synthesis of 2-chloro-N-{(1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}-6-(trifluoromethyl)isonicotinamide (example I-20)

Step 1: methyl 2-(5-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}-3-methyl-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxylate

[0522] ##STR00037##

[0523] To a solution of 3.28 g (17.4 mmol)N-(tert-butoxycarbonyl)-L-alaninamide in 32 ml dry dichloromethane was added 3.82 g (26.1 mmol) 1,1-dimethoxy-N,N-dimethylethanamine and the mixture was refluxed for 90 minutes. After cooling to room temperature, the mixture was evaporated under vacuo and the residue was diluted in 24.5 ml 1,4-dioxane and 24.5 ml acetic acid. 3.68 g (21.2 mmol) methyl 2-hydrazino-1,3-thiazole-5-carboxylate was added and the reaction mixture stirred at 50° C. overnight. The mixture was diluted with water and ethyl acetate and then the organic layer was washed with brine and sat. aq. Na.sub.2CO.sub.3, dried over Na.sub.2SO.sub.4 and evaporated under vacuo to give a residue which was purified by reversed-phase chromatography (H.sub.2O/acetonitrile) to yield the title compound (3.30 g) which was used in the next step without further purification.

[0524] .sup.1H-NMR peak list (400 MHz, DMSO-d6) δ=8.2074 (4.7); 5.7037 (0.9); 5.6859 (1.0); 5.6664 (0.8); 5.4481 (2.7); 3.8825 (16.0); 2.3443 (14.0); 2.1655 (33.2); 2.1609 (28.0); 1.9649 (1.3); 1.9587 (1.5); 1.9530 (12.3); 1.9469 (23.1); 1.9407 (32.1); 1.9346 (22.3); 1.9284 (11.6); 1.4714 (6.3); 1.4542 (6.3); 1.3672 (4.1); 1.2901 (0.3); −0.0002 (1.8).

[0525] ESI mass [m/z]: 368.1 [M+H].sup.+

Step 2: 2-(5-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}-3-methyl-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxylic acid

[0526] ##STR00038##

[0527] To a solution of 3.76 g (10.2 mmol) methyl 2-(5-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}-3-methyl-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxylate in 40.0 ml THF and 4.0 ml water was added 860 mg (20.4 mmol) lithium hydroxide and the mixture was stirred at room temperature overnight. The mixture was evaporated under vacuo and then the residue was diluted with ethyl acetate and a 5% aq. NaH.sub.2PO.sub.4 solution. The aqueous phase was acidified to reach pH 3 with aq. 10% HCl and extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated to give the title compound (3.60 g) which was used in the next without further purification.

[0528] .sup.1H-NMR peak list (400 MHz, DMSO-d.sub.6) δ=8.2747 (5.0); 7.6045 (0.8); 7.5871 (0.9); 5.6001 (0.8); 5.5822 (1.0); 5.5646 (0.6); 4.0376 (0.7); 4.0199 (0.7); 3.3315 (13.2); 2.6763 (0.5); 2.6720 (0.7); 2.6674 (0.5); 2.5252 (2.4); 2.5116 (43.5); 2.5074 (86.1); 2.5029 (112.6); 2.4984 (85.0); 2.4943 (43.9); 2.3328 (15.0); 1.9893 (3.2); 1.9091 (1.0); 1.4111 (7.8); 1.3936 (7.9); 1.3403 (16.0); 1.2324 (1.6); 1.1931 (1.0); 1.1753 (1.9); 1.1694 (0.4); 1.1575 (1.0); 1.0733 (1.2); 0.1457 (0.5); 0.0078 (4.6); −0.0002 (116.2); −0.0084 (5.4); −0.1497 (0.5).

[0529] ESI mass [m/z]: 353.9 [M+H].sup.+

Step 3: tert-butyl {(1S)-1-[1-(5-carbamoyl-1,3-thiazol-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}carbamate

[0530] ##STR00039##

[0531] To a solution of 2.60 g (7.35 mmol) 2-(5-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}-3-methyl-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxylic acid in 28.6 ml THF was added 1.74 ml (12.5 mmol) triethylamine and the suspension was cooled to −20° C. Then 1.43 ml (11.0 mmol) isobutyl chloroformate was added slowly to the suspension at −20° C. The mixture was stirred for 15 minutes at −10° C. after which 1.11 ml (11.7 mmol) 33% aq. ammonia solution was added to the mixture. Stirring was continued for 1 h at room temperature. The mixture was then quenched with an aq. saturated Na.sub.2CO.sub.3 solution and extracted with ethyl acetate. The combined organic layers was washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by reversed-phase chromatography (H.sub.2O/acetonitrile) to give the title compound (2.10 g).

[0532] .sup.1H-NMR peak list (400 MHz, DMSO-d.sub.6) δ=8.2532 (10.1); 7.7577 (1.3); 7.5789 (0.8); 7.5606 (0.8); 5.5803 (0.9); 5.5630 (1.3); 5.5449 (0.8); 4.0559 (0.4); 4.0380 (1.3); 4.0202 (1.3); 4.0024 (0.4); 3.8502 (0.7); 3.8335 (0.7); 3.6844 (4.9); 3.6676 (5.0); 3.3337 (52.2); 2.6727 (0.4); 2.5261 (1.2); 2.5126 (23.0); 2.5082 (45.8); 2.5037 (59.8); 2.4991 (44.0); 2.4947 (21.7); 2.3245 (16.0); 1.9897 (5.6); 1.8465 (0.4); 1.8297 (0.8); 1.8130 (1.1); 1.7962 (0.9); 1.7795 (0.5); 1.4088 (7.7); 1.3914 (7.8); 1.3426 (15.2); 1.1934 (1.7); 1.1756 (3.2); 1.1578 (1.6); 1.0900 (1.0); 0.8963 (2.2); 0.8887 (0.4); 0.8766 (14.8); 0.8598 (14.1); 0.0079 (2.5); −0.0002 (64.9); −0.0085 (2.4).

[0533] ESI mass [m/z]: 353.3 [M+H].sup.+

Step 4: tert-butyl {(1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}carbamate

[0534] ##STR00040##

[0535] To a solution of 0.50 g (1.41 mmol) tert-butyl {(1S)-1-[1-(5-carbamoyl-1,3-thiazol-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}carbamate in 3.5 ml THF under argon was added 0.47 g (1.98 mmol) of Burgess reagent ((methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt) and the mixture was stirred at 70° C. for 1 h. The reaction mixture was evaporated, and the crude product was diluted with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic layers was washed with brine, dried over Na.sub.2SO.sub.4 and evaporated to give the title compound (0.48 g) which was used in the next step without further purification.

[0536] .sup.1H-NMR peak list (400 MHz, DMSO-d.sub.6) δ=8.6230 (4.9); 7.6291 (0.8); 7.6112 (0.8); 5.5668 (0.8); 5.5495 (1.2); 5.5314 (0.7); 4.0382 (0.8); 4.0204 (0.9); 3.8502 (0.4); 3.8334 (0.4); 3.5256 (0.4); 3.4733 (1.0); 3.3319 (16.7); 2.5081 (32.0); 2.5038 (40.2); 2.4994 (29.5); 2.3423 (13.4); 2.3187 (0.6); 1.9899 (3.5); 1.4100 (7.7); 1.3926 (7.7); 1.3420 (16.0); 1.1937 (1.4); 1.1760 (2.8); 1.1581 (1.5); 1.0851 (1.0); 0.8963 (1.3); 0.8791 (1.7); 0.8764 (2.0); 0.8594 (1.7); −0.0002 (21.8); −0.0082 (0.9).

[0537] ESI mass [m/z]: 335.1 [M+H].sup.+

Step 5: 2-{5-[(1S)-1-aminoethyl]-3-methyl-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carbonitrile hydrochloride (INT-2)

[0538] ##STR00041##

[0539] To a solution of 0.48 g (1.44 mmol) tert-butyl {(1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}carbamate in 15 ml 1,4-dioxane was added 6.75 ml (28.8 mmol) of a 4 M solution of HCl in 1,4-dioxane and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated, and the crude product was stirred with diethyl ether. The solid was removed by filtration and dried to give the title compound (0.25 g) which was used in the next step without further purification.

[0540] .sup.1H-NMR peak list (400 MHz, DMSO-d.sub.6) δ=8.7878 (2.3); 8.6835 (7.1); 5.3082 (0.4); 5.2912 (1.1); 5.2743 (1.1); 5.2577 (0.3); 3.5681 (2.4); 3.3381 (19.0); 2.6722 (0.3); 2.5255 (1.2); 2.5120 (21.3); 2.5077 (42.0); 2.5032 (54.6); 2.4986 (40.2); 2.4942 (20.0); 2.4237 (16.0); 2.4089 (0.5); 2.3300 (0.4); 1.6192 (6.0); 1.6022 (5.9); 1.1928 (0.6); 0.0080 (1.0); −0.0002 (26.0); −0.0085 (1.0).

[0541] ESI mass [m/z]: 235.2 [amine+H].sup.+

Step 6: 2-chloro-N-{(1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}-6-(trifluoromethyl)isonicotinamide (example I-20)

[0542] ##STR00042##

[0543] To a solution of 88 mg (0.38 mmol) 2-chloro-6-(trifluoromethyl)isonicotinic acid in 2.5 ml dry dichloromethane were added 169 mg (0.44 mmol) HATU and 0.09 ml (0.5 mmol) N,N-diisopropylethylamine. After 30 minutes stirring at room temperature a solution of 100 mg (0.36 mmol) 2-{5-[(1S)-1-aminoethyl]-3-methyl-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carbonitrile hydrochloride and 0.13 ml (0.73 mmol) N,N-diisopropylethylamine in 2.5 ml dichloromethane, which had been previously stirred for 30 minutes at room temperature, was added to the mixture. The reaction mixture was stirred or 16 h at room temperature. It was then diluted with a 5% aq. NaH.sub.2PO.sub.4 solution and extracted with dichloromethane. The combined organic layers were evaporated and the residue was purified by reversed-phase chromatography (H.sub.2O/acetonitrile) to give 129 mg of the title compound.

[0544] .sup.1H-NMR peak list (400 MHz, DMSO-d.sub.6): see table 1.

[0545] ESI mass [m/z]: 442.1 [M+H].sup.+

Synthesis of N-(cyanomethyl)-2-(5-{(1S)-1-[3-cyclopropyl-5-(trifluoromethoxy)benzamido]ethyl}-3-methyl-1H-1,2,4-triazol-1-yl)-N-methyl-1,3-thiazole-5-carboxamide (example I-24)

Step 1: tert-butyl [(1S)-1-(1-{5-[(cyanomethyl)(methyl)carbamoyl]-1,3-thiazol-2-yl}-3-methyl-1H-1,2,4-triazol-5-yl)ethyl]carbamate

[0546] ##STR00043##

[0547] To a solution of 1.12 g (3.17 mmol) 2-(5-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}-3-methyl-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxylic acid in 10.0 ml dry dichloromethane were added 1.45 g (3.80 mmol) HATU and 0.77 ml (4.4 mmol) N,N-diisopropylethylamine. After 30 minutes stirring at room temperature a solution of 355 mg (3.33 mmol) methylaminoacetonitrile hydrochloride and 0.66 ml (3.8 mmol) N,N-diisopropylethylamine in 4 ml dichloromethane, which had been previously stirred for 30 minutes at room temperature, was added and the reaction mixture stirred for 16 h at room temperature. The mixture was then diluted with a 5% aq. NaH.sub.2PO.sub.4 solution and extracted with dichloromethane. The combined organic layers were washed with a sat. aq. Na.sub.2CO.sub.3 and brine, dried over Na.sub.2SO.sub.4 and evaporated under vacuo. The residue was purified by column chromatography on silica gel (cyclohexane/ethylacetate) to yield the title compound (1.05 g) which was used in the next step without further purification.

[0548] .sup.1H-NMR peak list (400 MHz, DMSO-d.sub.6) δ=8.2379 (1.9); 7.6059 (0.9); 7.5884 (0.9); 5.6125 (0.8); 5.5946 (1.2); 5.5769 (0.7); 4.6148 (2.4); 4.0561 (0.8); 4.0383 (2.3); 4.0205 (2.3); 4.0027 (0.8); 3.3278 (33.1); 2.5257 (1.0); 2.5122 (21.0); 2.5079 (40.7); 2.5033 (52.3); 2.4988 (38.2); 2.4945 (18.8); 2.3343 (15.9); 2.3126 (0.6); 1.9895 (9.9); 1.6669 (0.5); 1.4235 (8.2); 1.4061 (8.1); 1.3453 (16.0); 1.3087 (0.9); 1.2767 (0.5); 1.1936 (2.9); 1.1758 (5.6); 1.1580 (2.8); 1.0838 (1.1); −0.0002 (5.5).

[0549] ESI mass [m/z]: 406.1 [M+H].sup.+

Step 2: 2-{5-[(1S)-1-aminoethyl]-3-methyl-1H-1,2,4-triazol-1-yl}-N-(cyanomethyl)-N-methyl-1,3-thiazole-5-carboxamide hydrochloride (INT-3)

[0550] ##STR00044##

[0551] To a solution of 1.05 g (2.59 mmol) tert-butyl [(1S)-1-(1-{5-[(cyanomethyl)(methyl)carbamoyl]-1,3-thiazol-2-yl}-3-methyl-1H-1,2,4-triazol-5-yl)ethyl]carbamate in 12.3 ml 1,4-dioxane was added 12.1 ml (51.7 mmol) of a 4 M solution of HCl in 1,4-dioxane and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to give the title compound (0.96 g) which was used in the next step without further purification.

[0552] .sup.1H-NMR peak list (400 MHz, DMSO-d.sub.6) δ=8.7134 (2.8); 8.3232 (0.4); 8.2848 (1.3); 8.2291 (0.4); 7.1668 (0.4); 5.3306 (0.8); 5.3158 (0.9); 4.6228 (1.5); 4.1433 (0.4); 4.0527 (0.7); 3.5681 (4.9); 3.3422 (123.1); 3.2988 (1.5); 2.9762 (0.7); 2.7750 (0.5); 2.6765 (0.8); 2.6721 (1.1); 2.6676 (0.8); 2.5253 (3.4); 2.5116 (71.0); 2.5075 (137.3); 2.5030 (180.1); 2.4985 (137.3); 2.4946 (70.8); 2.4216 (16.0); 2.4163 (6.9); 2.3345 (1.0); 2.3299 (1.2); 2.3254 (0.9); 2.3131 (0.6); 2.3064 (0.3); 1.6285 (6.8); 1.6116 (6.9); −0.0001 (0.6).

[0553] ESI mass [m/z]: 306.1 [amine+H].sup.+

Step 3: N-(cyanomethyl)-2-(5-{(1S)-1-[3-cyclopropyl-5-(trifluoromethoxy)benzamido]ethyl}-3-methyl-1H-1,2,4-triazol-1-yl)-N-methyl-1,3-thiazole-5-carboxamide (example I-24)

[0554] ##STR00045##

[0555] To a solution of 60.0 mg (0.24 mmol) 3-cyclopropyl-5-(trifluoromethoxy)benzoic acid in 2.0 ml dry dichloromethane were added 112 mg (0.30 mmol) HATU and 0.05 ml (0.3 mmol) N,N-diisopropylethylamine. After 30 minutes stirring at room temperature a solution of 88 mg (0.25 mmol) 2-{5-[(1S)-1-aminoethyl]-3-methyl-1H-1,2,4-triazol-1-yl}-N-(cyanomethyl)-N-methyl-1,3-thiazole-5-carboxamide and 0.05 ml (0.3 mmol) N,N-diisopropylethylamine in 2 ml dichloromethane, which had been previously stirred for 30 minutes, was added to the mixture. The reaction mixture was stirred for 16 h at room temperature, was then diluted with a 5% aq. NaH.sub.2PO.sub.4 solution and extracted with dichloromethane. The combined organic layers were washed with a sat. aq. Na.sub.2CO.sub.3 solution and brine, dried over Na.sub.2SO.sub.4 and evaporated under vacuo. The residue was purified by reversed-phase chromatography (H.sub.2O/acetonitrile) to yield the title compound (56 mg).

[0556] .sup.1H-NMR peak list (400 MHz, DMSO-d.sub.6): see table 1.

[0557] ESI mass [m/z]: 533.8 [M+H].sup.+

Synthesis of 2-(5-{(1S)-1-[3,5-bis(trifluoromethyl)benzamido]ethyl}-3-methyl-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxamide (example I-21)

Step 1: methyl 2-{5-[(1S)-1-aminoethyl]-3-methyl-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carboxylate hydrochloride (INT-5)

[0558] ##STR00046##

[0559] To a solution of 2.66 g (7.24 mmol) methyl 2-(5-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}-3-methyl-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxylate in 80.0 ml 1,4-dioxane was added 33.8 ml (145 mmol) of a 4 M solution of HCl in 1,4-dioxane and the mixture was stirred at room temperature overnight. The solid precipitate was removed by filtration and dried to give the title compound (1.4 g) which was used in the next step without further purification.

[0560] .sup.1H-NMR peak list (400 MHz, DMSO-d.sub.6) δ=8.6668 (2.5); 8.4540 (7.2); 5.3471 (0.4); 5.3301 (1.4); 5.3131 (1.4); 5.2961 (0.4); 3.8887 (15.9); 3.5681 (0.9); 3.3315 (108.4); 2.6760 (0.7); 2.6715 (1.0); 2.6669 (0.7); 2.6624 (0.4); 2.5250 (3.2); 2.5201 (5.2); 2.5114 (58.1); 2.5071 (114.9); 2.5025 (149.8); 2.4979 (110.0); 2.4935 (54.0); 2.4232 (16.0); 2.3339 (0.7); 2.3293 (1.0); 2.3248 (0.7); 1.6174 (5.9); 1.6005 (5.8); 0.1459 (0.7); 0.0080 (6.6); −0.0002 (171.4); −0.0085 (6.6); −0.1496 (0.7).

[0561] ESI mass [m/z]: 267.9 [amine+H].sup.+

Step 2: methyl 2-(5-{(1S)-1-[3,5-bis(trifluoromethyl)benzamido]ethyl}-3-methyl-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxylate

[0562] ##STR00047##

[0563] To a suspension of 1.4 g (4.6 mmol) methyl 2-{5-[(1S)-1-aminoethyl]-3-methyl-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carboxylate hydrochloride in 60 ml dichloromethane were added 1.93 ml (11.1 mmol) N,N-diisopropylethylamine and a solution of 1.40 g (5.07 mmol) 3,5-bis(trifluoromethyl)benzoyl chloride in 10 ml dichloromethane. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with a 5% aq. NaH.sub.2PO.sub.4 solution and extracted with dichloromethane. The combined organic layers were evaporated and the residue was absorbed in diatomaceous earth and then purified by column chromatography on silica gel (cyclohexane/ethyl acetate) to yield the title compound (2.17 g).

[0564] ESI mass [m/z]: 508.3 [M+H].sup.+

Step 3: 2-(5-{(1S)-1-[3,5-bis(trifluoromethyl)benzamido]ethyl}-3-methyl-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxylic acid

[0565] ##STR00048##

[0566] To a solution of 2.17 g (4.28 mmol) methyl 2-(5-{(1S)-1-[3,5-bis(trifluoromethyl)benzamido]ethyl}-3-methyl-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxylate in 23.1 ml THF and 2.3 ml water was added 359 mg (8.56 mmol) lithium hydroxide and the mixture was stirred at room temperature overnight. The mixture was evaporated under vacuo and then the residue was diluted with ethyl acetate and an aq. 10% hydrochloric acid solution followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated to give the title compound (2.1 g) which was used in the next step without further purification.

[0567] .sup.1H-NMR peak list (400 MHz, DMSO-d.sub.6) δ=9.6742 (1.4); 9.6574 (1.4); 8.5357 (5.0); 8.3427 (2.2); 8.2960 (7.6); 6.1147 (1.0); 6.0975 (1.6); 6.0803 (1.0); 4.0568 (0.4); 4.0390 (1.2); 4.0212 (1.2); 4.0034 (0.4); 3.3356 (3.6); 3.2797 (0.4); 2.6740 (0.4); 2.5274 (1.2); 2.5227 (1.9); 2.5140 (21.3); 2.5096 (42.5); 2.5050 (55.2); 2.5004 (40.4); 2.4959 (19.8); 2.3374 (16.0); 1.9907 (5.4); 1.9110 (4.3); 1.6426 (5.4); 1.6252 (5.4); 1.1942 (1.5); 1.1764 (3.0); 1.1702 (0.4); 1.1586 (1.5); 0.0080 (2.4); −0.0002 (64.9); −0.0085 (2.6).

[0568] ESI mass [m/z]: 494.1 [M+H].sup.+

Step 4: 2-(5-{(1S)-1-[3,5-bis(trifluoromethyl)benzamido]ethyl}-3-methyl-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxamide (example I-21)

[0569] ##STR00049##

[0570] To a solution of 209 mg (0.42 mmol) 2-(5-{(1S)-1-[3,5-bis(trifluoromethyl)benzamido]ethyl}-3-methyl-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxylic acid in 1.65 ml THF was added 0.10 ml (0.72 mmol) triethylamine and the suspension was cooled to −20° C. Then 0.08 ml (0.64 mmol) isobutyl chloroformate was added slowly to the suspension at −20° C. and the mixture was stirred for 15 minutes at −10° C. after which 0.06 ml (0.7 mmol) 33% aq. ammonia solution was added into the mixture. Stirring was continued for 1 h at room temperature. The mixture was then quenched with an aq. saturated Na.sub.2CO.sub.3 solution and extracted with ethyl acetate. The combined organic layers was washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by reversed-phase chromatography (H.sub.2O/acetonitrile) to give the title compound (0.13 g).

[0571] .sup.1H-NMR peak list (400 MHz, DMSO-d.sub.6): see table 1.

[0572] ESI mass [m/z]: 493.2 [M+H].sup.+

Synthesis of 2-(5-{(1S)-1-[3,5-bis(trifluoromethyl)benzamido]ethyl}-3-methyl-1H-1,2,4-triazol-1-yl)-N,N-dimethyl-1,3-thiazole-5-carboxamide (example I-5)

[0573] ##STR00050##

[0574] To a solution of 105 mg (0.21 mmol) 2-(5-{(1S)-1-[3,5-bis(trifluoromethyl)benzamido]ethyl}-3-methyl-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxylic acid in 3 ml dry dichloromethane were added 92 mg (0.24 mmol) HATU and 0.05 ml (0.3 mmol) N,N-diisopropylethylamine. After 30 minutes stirring at room temperature 0.1 mL (0.20 mmol) of a 2 M solution of dimethylamine in THF diluted with 1 ml dichloromethane was added to the mixture. The reaction mixture was stirred overnight, then diluted with a 5% aq. NaH.sub.2PO.sub.4 solution and extracted with dichloromethane. The combined organic layers were washed with a sat. aq. Na.sub.2CO.sub.3 solution and brine, dried over Na.sub.2SO.sub.4 and evaporated under vacuo. The residue was purified by reversed-phase chromatography (H.sub.2O/acetonitrile) to yield the title compound (90 mg).

[0575] .sup.1H-NMR peak list (400 MHz, DMSO-d.sub.6): see table 1.

[0576] ESI mass [m/z]: 521.4 [M+H].sup.+

Synthesis of tert-butyl {(1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}carbamate

Step 1: 2-hydrazino-1,3-thiazole-5-carbonitrile

[0577] ##STR00051##

[0578] A mixture of 9.00 g (62.2 mmol) 2-chloro-1,3-thiazole-5-carbonitrile and 124.5 ml (124.5 mmol) of a 1 M solution of hydrazine in THF was refluxed for 2 h. After cooling to room temperature, the mixture was evaporated and then the residue was suspended in 50 ml of hot water. The resulting precipitate was filtered, washed with water and dried under vacuo to yield the title compound (9.00 g). Further drying by co-evaporation with absolute toluene resulted in a decrease in mass and this material was used in the next step.

[0579] .sup.1H NMR peak list (DMSO-d.sub.6, 400 MHz): δ=9.7694 (1.7); 7.8727 (13.8); 5.3331 (16.0); 3.3330 (6.9); 2.5083 (12.7); 2.5040 (16.5); 2.4997 (12.5)

[0580] ESI mass [m/z]: 141.0 [M+H].sup.+

Step 2: tert-butyl {(1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}carbamate

[0581] ##STR00052##

[0582] To a solution of 0.500 g (2.65 mmol) N.sup.2-(tert-butoxycarbonyl)-L-alaninamide in 17 mL CH.sub.2Cl.sub.2 were added 0.53 mL (4.0 mmol) N,N-dimethylformamide dimethylacetal. The solution was heated at reflux for 2 h after which the solvent was removed under reduced pressure. The residue was dissolved in a mixture of 10 mL glacial acetic acid and 10 mL 1,4-dioxane. 0.596 g (4.25 mmol) 2-hydrazino-1,3-thiazole-5-carbonitrile were added and the mixture was stirred for 1 h at 50° C. The solvent was then removed under reduced pressure, a saturated aq. NaHCO.sub.3 solution was added and the mixture repeatedly extracted with ethyl acetate. The combined organic layers were washed with brine, dried with Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica (ethyl acetate/cyclohexane) to provide 356 mg of tert-butyl {(1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}carbamate.

[0583] The enantiomeric excess of the chiral title compound was determined via chiral chromatography in comparison with the racemate: ee-value=84%; R.sub.t=11.80 min.

[0584] .sup.1H NMR peak list (DMSO-d.sub.6, 400 MHz): δ=8.6600 (4.0); 8.2923 (2.2); 7.6953 (0.8); 7.6777 (0.8); 5.5940 (0.6); 5.5771 (0.8); 5.5591 (0.6); 3.3345 (44.8); 2.8917 (0.5); 2.7322 (0.4); 2.6766 (0.4); 2.6721 (0.5); 2.6676 (0.4); 2.5253 (1.7); 2.5119 (31.6); 2.5076 (60.4); 2.5031 (78.1); 2.4986 (58.0); 2.4944 (28.8); 2.3345 (0.4); 2.3300 (0.5); 2.3255 (0.4); 1.9897 (0.7); 1.9092 (0.5); 1.4244 (7.1); 1.4069 (7.1); 1.3706 (0.6); 1.3363 (16.0); 1.1752 (0.5); 1.0697 (1.0); 0.0078 (2.3); −0.0002 (50.8); −0.0085 (2.0)

[0585] ESI mass [m/z]: 265.0 [M−C.sub.4H.sub.8+H].sup.+

[0586] The tert-butoxycarbonyl group is removed by treatment with HCl in dioxane to yield 2-{5-[(1S)-1-aminoethyl]-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carbonitrile hydrochloride (1:1) (see synthesis of 2-{5-[(1S)-1-aminoethyl]-3-methyl-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carbonitrile hydrochloride described in this application).

Alternative procedure for the synthesis of tert-butyl {(1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}carbamate

[0587] ##STR00053##

[0588] To a solution of 1.00 g (5.31 mmol) N.sup.2-(tert-butoxycarbonyl)-L-alaninamide in 17 mL 1,4-dioxane were added 0.78 mL (5.8 mmol) N,N-dimethylformamide dimethylacetal. The solution was heated at 40° C. for 2.5 h. The reaction mixture was cooled to room temperature. 17 mL glacial acetic acid and 0.894 g (6.37 mmol) 2-hydrazino-1,3-thiazole-5-carbonitrile were added and the mixture was stirred overnight at room temperature. The solvents were then removed under reduced pressure and the residue was purified by chromatography on silica (ethyl acetate/cyclohexane) to provide 1.23 g of tert-butyl {(1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}carbamate.

[0589] The enantiomeric excess of the chiral title compound was determined via chiral chromatography in comparison with the racemate: ee-value>99%; R.sub.t=11.79 min.

[0590] [α].sub.D.sup.20=+18 (c=1.15; ethanol)

Synthesis of tert-butyl {1-[1-(5-cyano-1,3-thiazol-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}carbamate

[0591] ##STR00054##

[0592] To a solution of 0.25 g (1.33 mmol) N.sup.2-(tert-butoxycarbonyl)-alaninamide in 8.5 mL CH.sub.2Cl.sub.2 were added 0.26 mL (2.0 mmol) N,N-dimethylformamide dimethylacetal. The solution was heated at reflux for 1 h after which the solvent was removed under reduced pressure. The residue was dissolved in 8.4 mL glacial acetic acid. 0.22 g (1.6 mmol) 2-hydrazino-1,3-thiazole-5-carbonitrile were added and the mixture was stirred for 2 h at 80° C. The solvent was then removed under reduced pressure, water was added and the mixture repeatedly extracted with ethyl acetate. The combined organic layers were consecutively washed with a sat. aq. solution of NaHCO.sub.3 and brine, dried with Na.sub.2SO.sub.4 and then the solvent was removed under reduced pressure. The residue was purified by chromatography on silica (ethyl acetate/cyclohexane) to provide 224 mg of tert-butyl {1-[1-(5-cyano-1,3-thiazol-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}carbamate.

[0593] ESI mass [m/z]: 265.0 [M−C.sub.4H.sub.8+H].sup.+

Synthesis of 3-chloro 5-(pentafluoroethyl)benzoic acid

Step 1: methyl 3-chloro-5-(pentafluoroethyl)benzoate

[0594] ##STR00055##

[0595] To methyl 3-chloro-5-iodo-benzoate (18.5 g, 62.4 mmol) in DMF (180 mL) was added the potassium salt of pentafluoropropionic acid (22.7 g, 112.3 mmol) and CuI (23.7 g, 124.8 mmol) and the mixture was stirred at 160° C. for 2 h, monitored by TLC. Water (200 mL) and EtOAc (300 mL) were added to the reaction mixture, the resulting suspension was filtered and the organic phase was separated from the filtrate. The organic phase was washed with H.sub.2O (2×50 mL) and then concentrated. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=I/O to 100/1). The title compound was obtained as red oil (10.0 g, 32.2 mmol, 51.6% yield, 93.0% purity).

[0596] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=8.24 (s, 1H), 8.17 (s, 1H), 7.78 (s, 1H), 3.98 (s, 3H). Measured using a Bruker 400 MHz NMR machine.

Step 2: 3-chloro-5-(pentafluoroethyl)benzoic acid

[0597] ##STR00056##

[0598] Methyl 3-chloro 5-(pentafluoroethyl)benzoate (10.0 g, 34.6 mmol) was dissolved in MeOH (50 mL). LiOH (1.66 g, 69.3 mmol) in H.sub.2O (50 mL) was added to the above solution, the mixture was stirred at 25° C. for 5 h, monitored by TLC. Water (100 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (60 mL). The separated water phase was acidified with 1N HCl until pH=5-6, then the solution was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated. The title compound was obtained as white solid (8.00 g, 29.1 mmol, 84.0% yield).

[0599] .sup.1H-NMR (400 MHz, MeOD): δ=8.24 (s, 1H), 8.14 (s, 1H), 7.88 (s, 1H). Measured using a Bruker 400 MHz NMR machine.

[0600] ESI mass [m/z]: 272.9 [M].sup.+

Synthesis of 3-(difluoromethyl)-5-(trifluoromethoxy)benzoic acid

Step 1: 1-bromo-3-(difluoromethyl)-5-(trifluoromethoxy)benzene

[0601] ##STR00057##

[0602] To a solution of 5.00 g (18.5 mmol) 3-bromo-5-(trifluoromethoxy)benzaldehyde in 100 ml CH.sub.2Cl.sub.2 were added 3.0 mL (23 mmol) diethylaminosulfur trifluoride. The reaction mixture was stirred for 2 h at room temperature. After this time the reaction mixture was quenched with a sat. aq. solution of NaHCO.sub.3 and extracted with CH.sub.2Cl.sub.2. The combined organic layers were dried with Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. Analysis of the crude product by NMR revealed the incomplete conversion of the starting material. Therefore the residue was re-dissolved in 100 ml CH.sub.2Cl.sub.2 and 3.0 mL (23 mmol) diethylaminosulfur trifluoride were added. Stirring was continued until the full conversion of the starting material was observed by analytical HPLC. The reaction mixture was quenched with a sat. aq. solution of NaHCO.sub.3 and extracted with CH.sub.2Cl.sub.2. The combined organic layers were dried with Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford 4.87 g of a residue containing 1-bromo-3-(difluoromethyl)-5-(trifluoromethoxy)benzene. A portion of this crude material was purified by chromatography on silica (cyclohexane/EtOAc) to provide 1.78 g of pure 1-bromo-3-(difluoromethyl)-5-(trifluoromethoxy)-benzene. This was used for the following carbonylation reaction.

[0603] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): δ=7.92 (s, 1H), 7.88 (s, 1H), 7.65 (s, 1H), 7.10 (t, J=55 Hz, 1H).

[0604] EI mass [m/z]: 290, 292 [M].sup.+

Step 2: methyl 3-(difluoromethyl)-5-(trifluoromethoxy)benzoate

[0605] ##STR00058##

[0606] To a solution of 1.78 g (6.11 mmol) 1-bromo-3-(difluoromethyl)-5-(trifluoromethoxy)benzene in 45 mL methanol were added 1.51 g (18.3 mmol) sodium acetate and 0.15 g (0.18 mmol) dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) acetone adduct. This solution was then stirred for 16 h at 80° C. in an autoclave under a carbon monoxide (5 bar) atmosphere. After this time full conversion of the starting material to methyl 3-(difluoromethyl)-5-(trifluoromethoxy)benzoate was observed. The reaction mixture was used directly in the next step.

[0607] EI mass [m/z]: 270 [M].sup.+

Step 3: 3-(difluoromethyl)-5-(trifluoromethoxy)benzoic acid

[0608] ##STR00059##

[0609] To the solution from the first step was added 70 mL THF and 5.3 mL of a 45% aqeuous sodium hydroxide solution. The mixture was heated under reflux for 45 min after which it was acidified to pH 1-2 using conc. hydrochloric acid. A precipitate formed which was removed by filtration. The filtrate was evaporated to dryness. Water was added to the residue and the mixture extracted repeatedly with diethyl ether. The combined organic layers were washed with brine, dried with Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 1.44 g methyl 3-(difluoromethyl)-5-(trifluoromethoxy)benzoate.

[0610] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): δ=13.8 (brs, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.20 (t, J=55 Hz, 1H).

[0611] ESI mass [m/z]: 254.8 [M−H].sup.−

Synthesis of 3-(difluoromethoxy)-5-(difluoromethyl)benzoic acid

Step 1: methyl 3-(chlorocarbonyl)-5-(difluoromethoxy)benzoate

[0612] ##STR00060##

[0613] 3-(Difluoromethoxy)-5-(methoxycarbonyl)benzoic acid (known from WO 2012019428 (7.38 g, 30 mmol) was suspended in dry toluene (30 mL). Oxalyl chloride (5.71 g, 45 mmol) was added in one portion followed by one drop of DMF at room temperature. The reaction mixture was stirred at room temperature for 12 h and then at 60-70° C. for 2 h. The reaction mixture was evaporated to obtain 7.9 g of crude methyl 3-(chlorocarbonyl)-5-(difluoromethoxy)benzoate which is to use without further purification.

Step 2: methyl 3-(difluoromethoxy)-5-formylbenzoate

[0614] ##STR00061##

[0615] 2,6-Lutidine (3.38 g, 3.68 mL, 31.5 mmol) and 3-(chlorocarbonyl)-5-(difluoromethoxy)benzoate from step 1 (7.94 g, 30 mmol) were dissolved in absolute THF (100 mL), Pd/C (Alfa, dry, 10%, 430 mg) was added and the mixture was hydrogenated for 48 h (balloon with H.sub.2). The resulting precipitate was filtered off, washed with diethyl ether (200 mL) and saturated aqueous solution of NaHCO.sub.3 (30 mL) was added to the filtrate and stirred for 12 h at room temperature. The solution was diluted with further diethyl ether (300 mL) and water (300 mL). The organic layer was separated, washed with water (2×300 mL), an aqueous solution of citric acid (5%, 200 mL), water (300 mL) and brine (300 mL). The volatiles were removed in vacuo to obtain crude methyl 3-(difluoromethoxy)-5-formylbenzoate (4.1 g, 59% yield).

[0616] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=10.05 (d, J=0.7 Hz, 1H), 8.41-8.35 (m, 1H), 8.07-8.00 (m, 1H), 7.86-7.79 (m, 1H), 6.62 (t, J=72.4 Hz, 1H), 3.98 (d, J=0.7 Hz, 3H). Measured using a Varian Gemini 2000 machine.

Step 3: methyl 3-(difluoromethoxy)-5-(difluoromethyl)benzoate

[0617] ##STR00062##

[0618] Crude methyl 3-(difluoromethoxy)-5-formylbenzoate (4 g, 17.38 mmol) was dissolved in DCM (100 mL) and the solution was cooled down to −20° C. DAST (5.60 g, 34.8 mmol) was added in one portion and the reaction mixture was stirred for 12 h (slow warming up to room temperature). The reaction mixture was poured into a saturated aqueous solution of NaHCO.sub.3 (200 mL) and DCM (100 mL) was added, followed by separation of the organic layer, washing with water (100 mL) and drying over Na.sub.2SO.sub.4. The volatiles were removed in vacuo to obtain 4.5 g of crude methyl 3-(difluoromethoxy)-5-(difluoromethyl)benzoate as a brown oil.

[0619] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=8.04 (t, J=1.4 Hz, 1H), 7.92-7.87 (m, 1H), 7.48 (s, 1H), 6.68 (t, J=55.9 Hz, 1H), 6.59 (t, J=72.6 Hz, 1H), 3.96 (s, 3H). Measured using a Varian Gemini 2000 machine.

Step 4: 3-(difluoromethoxy)-5-(difluoromethyl)benzoic acid

[0620] ##STR00063##

[0621] A solution of LiOH (1.43 g, 34 mmol) in water (10 mL) was added to a solution of crude methyl 3-(difluoromethoxy)-5-(difluoromethyl)benzoate from step 3 (4.3 g, 17 mmol) in a mixture of THF (35 mL) and MeOH (35 mL). The reaction mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo, water (100 mL) was added and the resulting mixture was extracted with diethyl ether (100 mL). The separated aqueous layer was added dropwise into diluted HCl (5%, 100 mL). The precipitate was filtered off, washed with water, dried at 100° C. for 2 h and finally sublimed at 105° C. (0.1 torr) to obtain the title compound (3.2 g, 79% yield).

[0622] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): δ=13.62 (s, 1H), 7.99 (t, J=1.3 Hz, 1H), 7.82 (s, 1H), 7.70-7.62 (m, 1H), 7.42 (t, J=73.3 Hz, 1H), 7.15 (t, J=55.4 Hz, 1H). Measured using a Varian Gemini 2000 machine.

Synthesis of 3-chloro-5-(difluoromethyl)benzoic acid

Step 1: 3-chloro-5-(difluoromethyl)benzonitrile

[0623] ##STR00064##

[0624] A solution of 5.00 g (30.1 mmol) 3-chloro-5-formylbenzonitrile in 150 mL CH.sub.2Cl.sub.2 was treated with 5.84 g (36.2 mmol) diethylaminosulfur trifluoride (DAST) and stirred for 2 h at room temperature. The reaction was quenched by the careful addition of a sat. NaHCO.sub.3 solution and the mixture extracted repeatedly with CH.sub.2Cl.sub.2. The combined organic layers were washed with brine and dried with Na.sub.2SO.sub.4. The solvent was removed under reduced pressure to provide 5.31 g 3-chloro-5-(difluoromethyl)benzonitrile which was used without further purification.

[0625] EI mass [m/z]: 187 [M].sup.+

Step 2: 3-chloro-5-(difluoromethyl)benzoic acid

[0626] ##STR00065##

[0627] A solution of 300 mg (1.59 mmol) 3-chloro-5-(difluoromethyl)benzonitrile in a mixture of 6.5 mL THF and 3.5 mL methanol was treated with 1.92 g (23.9 mmol) of a 50% aq. solution of sodium hydroxide. The mixture was heated to reflux and stirred for 45 min at that temperature. All volatiles were then removed under reduced pressure. Water was added and the pH adjusted to pH 1 using concentrated hydrochlorid acid. The mixture was repeatedly extracted with EtOAc. The combined organic layers were washed with brine, dried with Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure to provide 278 mg of 3-chloro-5-(difluoromethyl)benzoic acid which was used without further purification in the synthesis of example II-12.

[0628] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): 13.65 (brs, 1H), 8.06 (s, 2H), 7.93 (s, 1H), 7.14 (t, J=55 Hz, 1H).

[0629] ESI mass [m/z]: 207.1 [M+H].sup.+

Synthesis of 3-cyclopropyl-5-(difluoromethoxy)benzoic acid

Step 1: methyl 3-bromo-5-hydroxybenzoate

[0630] ##STR00066##

[0631] A solution of 3-bromo-5-hydroxybenzoic acid (49.9 g, 230 mmol) in MeOH (325 mL) was cooled by an ice bath to 7-8° C. Then SOCl.sub.2 (27.4 g, 16.79 mL, 230 mmol) was added dropwise to this solution over 25 min. The reaction mixture was warmed to room temperature, stirred under reflux for 3 h, cooled down to room temperature and then stirred for another 48 h at this temperature. All volatiles were removed in vacuo and the residue dissolved in ethyl acetate (400 mL). The solution was washed with NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4 and the volatiles were removed under reduced pressure. The residue was triturated with hexanes (400 mL). The precipitate was filtered off, washed with hexanes/diethyl ether (1:1), dried at 110° C. to afford methyl 3-bromo-5-hydroxybenzoate (50.5 g) as a dark yellow powder.

[0632] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.73 (m, 1H), 7.51 (m, 1H), 7.26 (s, 1H), 7.23 (t, J=2.1 Hz, 1H), 6.05 (br s, 1H), 3.92 (s, 3H). (recorded on a Varian Gemini 2000 machine)

Step 2: methyl 3-bromo-5-(difluoromethoxy)benzoate

[0633] ##STR00067##

[0634] A mixture of methyl 3-bromo-5-hydroxybenzoate (23.1 g, 100 mmol), K.sub.2CO.sub.3 (41.5 g, 300 mmol) and ClF.sub.2CCOONa (45.7 g, 300 mmol) in DMF (350 mL) was stirred at 60-65° C. for 2 h. The precipitate was then separated, washed with acetone and the filtrate was evaporated under reduced pressure. The residue was dissolved in diethyl ether (300 mL) and the solution was left to stand at rt for 12 h. A precipitate formed which was filtered off and washed with water. The filtrate was washed with brine (300 mL) and the organic layer was evaporate under reduced pressured. The oily residue was dissolved in hexanes (250 mL) and kept at rt for 2 h. A precipitate formed which was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was distilled under reduced pressure (3 tor) and the fraction with a boiling point between 80 and 85° C. was collected to afford 15.75 g methyl 3-bromo-5-(difluoromethoxy)benzoate.

[0635] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.03 (t, J=1.6 Hz, 1H), 7.75-7.70 (m, 1H), 7.49 (t, J=2.1 Hz, 1H), 6.55 (t, J=72.6 Hz, 1H), 3.93 (s, 3H). (recorded on a Varian Gemini 2000 machine)

[0636] .sup.19F NMR (376 MHz, CDCl.sub.3) δ=−84.89 (d, J=72.7 Hz). (recorded on a Varian Gemini 2000 machine)

Step 3: 3-cyclopropyl-5-(difluoromethoxy)benzoic acid

[0637] ##STR00068##

[0638] A mixture of methyl 3-bromo-5-(difluoromethoxy)benzoate (12.07 g, 52 mmol), K.sub.3PO.sub.4 (27.6 g, 130 mmol), Ph.sub.3P (1.364 g, 5.2 mmol) and cyclopropylboronic acid (8.93 g, 104 mmol) in diglyme (250 mL) was heated to 100° C. and then (Ph.sub.3P).sub.2PdCl.sub.2 (1.825 g, 2.6 mmol) was added in one portion. The reaction mixture was stirred at 100° C. for 3 h, cooled down to rt and treated with a solution of NaOH (5 g) in water (250 mL). The reaction mixture was stirred for 48 h. Then the precipitate was filtered off and water 950 mL was added. The mixture was extracted with ethyl acetate (2×500 mL). The aqueous layer was acidified by concentrated hydrochloric acid to pH=2 and kept at rt for 12 h. The precipitate was filtered of, washed with boiling water (4×200 mL), dried at 110° C. to get 10.4 g of crude product. This material was dissolved in hot toluene (30 mL) and the solution was diluted by hexanes to 150 mL. The mixture was filtrated hot, the filtrate cooled down to room temperature and than left in the refrigerator for 3 h. A precipitate formed which was filtered off, washed with hexanes and dried at 110° C. to get 7.7 g of crude material. The mother liquor was evaporated and the residue triturated with hexanes:diethyl ether (1:1). The insoluble material was filtered off and combined with the 7.7 g crude material. The combined crude material was purified by sublimation (0.3 torr, 110° C.) to afford 9.7 g 3-cyclopropyl-5-(difluoromethoxy)benzoic acid.

[0639] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=12.10 (s, 1H), 7.67 (d, J=1.6 Hz, 1H), 7.62 (t, J=1.9 Hz, 1H), 7.08 (t, J=2.0 Hz, 1H), 6.55 (t, J=73.5 Hz, 1H), 2.06-1.89 (m, 1H), 1.15-0.96 (m, 2H), 0.85-0.69 (m, 2H). (recorded on a Varian Gemini 2000 machine)

[0640] .sup.19F NMR (376 MHz, CDCl.sub.3) δ=−84.24 (d, J=73.5 Hz). (recorded on a Varian Gemini 2000 machine)

Synthesis of 3-(difluoromethyl)-5-(methylsulfonyl)benzoic acid (INT-8)

Step 1: 3-(difluoromethyl)-5-(methylsulfanyl)benzonitrile

[0641] ##STR00069##

[0642] To a mixture of 0.24 g (5.5 mmol) sodium hydride and 13.6 mL DMF were added at 20° C. 2.30 g (11.0 mmol) 3-chloro-5-(difluoromethyl)benzonitrile. The mixture was stirred for 15 min at 20° C. after which 1.01 g (14.3 mmol) sodium methanethiolate were added. The reaction mixture was then stirred for 3 h at 50° C. The reaction was quenched by the careful addition of water and the reaction mixture acidified to pH 6 by the addition of acetic acid. All volatiles were then removed under reduced pressure. Water was added to the residue and the mixture repeatedly extracted with ethyl acetate. The combined organic layers were washed with brine and dried with Na.sub.2SO.sub.4. The solvent was removed under reduced pressure to provide a residue which was purified by reversed-phase chromatography (H.sub.2O/acetonitrile) to yield the title compound (497 mg) and 3-(difluoromethyl)-5-(methylsulfanyl)benzamide (287 mg).

[0643] ESI mass [m/z]: 200.1 [M+H].sup.+

Step 2: 3-(difluoromethyl)-5-(methylsulfanyl)benzoic acid

[0644] ##STR00070##

[0645] 497 mg (2.49 mmol) 3-(difluoromethyl)-5-(methylsulfanyl)benzonitrile were dissolved in 5.1 mL methanol and 10.1 mL THF. To this solution were added 1.98 mL of a 50% aqueous solution of sodium hydroxide and the reaction mixture was heated at reflux for 45 min. At this point 287 mg (1.32 mmol) 3-(difluoromethyl)-5-(methylsulfanyl)benzamide (obtained in the previous step) and further 1.98 ml of a 50% aqueous solution of sodium hydroxide solution were added. The mixture was heated at reflux for 1 h and stirred overnight at room temperature. All volatiles were removed under reduced pressure. Water was added. Then the mixture was acified to pH 1-2 using conc. hydrochloric acid after which it was repeatedly extracted with ethyl acetate. The combined organic layers were washed with brine and dried with Na.sub.2SO.sub.4. The solvent was removed under reduced pressure to provide 811 mg of a residue containing 3-(difluoromethyl)-5-(methylsulfanyl)benzoic acid.

[0646] ESI mass [m/z]: 219.1 [M+H].sup.+

Step 3: 3-(difluoromethyl)-5-(methylsulfonyl)benzoic acid (INT-8)

[0647] ##STR00071##

[0648] The crude material from the previous step containing 3-(difluoromethyl)-5-(methylsulfanyl)benzoic acid was dissolved in 40 mL CH.sub.2Cl.sub.2. Subsequently 0.7 mL formic acid and 2.7 mL of an aqeuous 30% hydrogen peroxide solution were added. The suspension was stirred overnight at room temperature after which further 0.7 mL formic acid and 2.7 mL 30% hydrogen peroxide solution were added. The suspension was stirred for 1 h at room temperature and for 1 h at 30° C. As the conversion of the starting material was still incomplete further 0.7 mL formic acid and 2.7 mL 30% hydrogen peroxide solution were added and the reaction mixture was stirred for 3 d at room temperature. At this point a 513 mg (2.97 mmol) meta-chloroperoxybenzoic acid were added and the mixture stirred further overnight at room temperature. It was then quenched by the addition of 40% aqueous NaHSO.sub.3 solution followed by stirring for 1 h. Water was added and the mixture repeatedly extracted with CH.sub.2Cl.sub.2. The combined organic layers were washed with brine and dried with Na.sub.2SO.sub.4. The solvent was removed under reduced pressure to provide a residue which was purified by reversed-phase chromatography (H.sub.2O/acetonitrile) to yield 3-(difluoromethyl)-5-(methylsulfonyl)benzoic acid (244 mg) and some recovered starting material (79 mg).

[0649] ESI mass [m/z]: 251.0 [M+H].sup.+

[0650] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ=14.0 (br s, 1H), 8.54 (s, 1H), 8.41 (s, 1H), 8.33 (s, 1H), 7.27 (t, J=55 Hz, 1H). (Signal of CH.sub.3-group is hidden under solvent signal)

Synthesis of 3-(cyclopropylsulfanyl)-5-(difluoromethyl)benzonitrile

Step 1: 3-(difluoromethyl)-5-fluorobenzonitrile

[0651] ##STR00072##

[0652] In a plastic reaction vessel 10 g (67 mmol) 3-fluoro-5-formylbenzonitrile were dissolved in 300 mL CH.sub.2Cl.sub.2. At room temperature 10.6 mL (80.4 mmol) diethylaminosulfur trifluoride were added and the mixture was stirred overnight. To the reaction mixture was then carefully added a sat. aqueous solution of NaHCO.sub.3. The mixture was stirred at room temperature until any remaining reagents had decomposed.

[0653] The mixture was then extracted with CH.sub.2Cl.sub.2. The combined organic layers were washed with brine, dried with Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to provide 10.67 g 3-(difluoromethyl)-5-fluorobenzonitrile which was used for the next step without further purification.

[0654] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ=8.10 (d, J=8 Hz, 1H), 7.99 (s, 1H), 7.89 (d, J=8 Hz, 1H), 7.11 (t, J=55 Hz, 1H).

Step 2: 3-(cyclopropylsulfanyl)-5-(difluoromethyl)benzonitrile

[0655] ##STR00073##

[0656] To a solution of 3.50 g (20.4 mmol) 3-(difluoromethyl)-5-fluorobenzonitrile in 40 mL DMF were added at 0° C. 2.95 g (30.6 mmol) sodium cyclopropanethiolate. The mixture was stirred for 1 h at 0° C. and overnight at room temperature. The reaction mixture was then concentrated under reduced pressure and the residue purified by reversed-phase chromatography (H.sub.2O/acetonitrile) to yield 3-(cyclopropylsulfanyl)-5-(difluoromethyl)benzonitrile (1.18 g) and some remaining 3-(difluoromethyl)-5-fluorobenzonitrile benzamide (582 mg).

[0657] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ=7.99 (s, 1H), 7.84 (s, 2H), 7.08 (t, J=55 Hz, 1H), 2.45-2.38 (m, 1H), 1.22-1.15 (m, 2H), 0.67-0.60 (m, 2H).

[0658] ESI mass [m/z]: 226.0 [M+H].sup.+

[0659] 3-(cyclopropylsulfanyl)-5-(difluoromethyl)benzonitrile was then further converted to 3-(cyclopropylsulfonyl)-5-(difluoromethyl)benzoic acid (INT-15) via hydrolysis of the nitrile and oxidation of the thioether to the sulfone. These transformations were conducted in analogy to the conditions described above for the synthesis of 3-(difluoromethyl)-5-(methylsulfonyl)benzoic acid (INT-8).

Synthesis of 3-(difluoromethoxy)-5-(methylsulfonyl)benzoic acid

Step 1: 3-(difluoromethoxy)-5-(methylsulfanyl)benzonitrile

[0660] ##STR00074##

[0661] To a solution of 0.90 g (4.8 mmol) 3-(difluoromethoxy)-5-fluorobenzonitrile (obtained from FCH Group) in 10 mL DMF at 0° C. were added 0.34 g (4.8 mmol) sodium methanethiolate. The mixture was stirred for 2 h at 0° C. after which it was allowed to warm to room temperature. The reaction mixture was stirred for 50 h at room temperature and then recooled to 0° C. Further 50 mg (0.7 mmol) sodium methanethiolate were added and the reaction mixture stirred for 1 h at 0° C. As the conversion was still incomplete further 15 mg (0.2 mmol) sodium methanethiolate were added and the reaction mixture was stirred for 30 min at 0° C. Water was then added and the reaction mixture acidified to pH 5 by the addition of acetic acid. All volatiles were removed under reduced pressure. Water was added to the residue and the mixture repeatedly extracted with ethyl acetate. The combined organic layers were washed with brine and dried with Na.sub.2SO.sub.4. The solvent was removed under reduced pressure to provide 1.41 g of a residue containing 3-(difluoromethoxy)-5-(methylsulfanyl)benzonitrile and residual DMF.

[0662] ESI mass [m/z]: 216.0 [M+H].sup.+

Step 2: 3-(difluoromethoxy)-5-(methylsulfanyl)benzoic acid

[0663] ##STR00075##

[0664] 1.10 g of the residue obtained in step one containing 3-(difluoromethoxy)-5-(methylsulfanyl)benzonitrile were dissolved in 8.3 mL methanol and 16.6 mL THF. To this solution were added 3.25 mL of a 50% aqueous solution of sodium hydroxide and the reaction mixture was heated at reflux for 2 h. Water was added at room temperature. The mixture was then acidified to pH 1-2 using conc. hydrochloric acid and repeatedly extracted with ethyl acetate. The combined organic layers were washed with brine and dried with Na.sub.2SO.sub.4. The solvent was removed under reduced pressure to provide a residue which was purified by reversed-phase chromatography (H.sub.2O/acetonitrile) to yield 592 mg 3-(difluoromethoxy)-5-(methylsulfanyl)benzoic acid.

[0665] ESI mass [m/z]: 235.0 [M+H].sup.+

Step 3: 3-(difluoromethoxy)-5-(methylsulfonyl)benzoic acid (INT-9)

[0666] ##STR00076##

[0667] To a solution of 85 mg (0.36 mmol) 3-(difluoromethoxy)-5-(methylsulfanyl)benzoic acid dissolved in 4 mL CH.sub.2Cl.sub.2 were added 0.07 mL formic acid and 288 mg of an aqeuous 30% hydrogen peroxide solution. The reaction mixture was stirred overnight at room temperature. It was then quenched by the addition of 40% aqueous NaHSO.sub.3 solution followed by stirring for 1 h. Water was added and the mixture extracted once with CH.sub.2Cl.sub.2 and repeatedly with ethyl acetate. The solvent was removed from the combined organic layers under reduced pressure to provide a residue which was purified twice by reversed-phase chromatography (H.sub.2O/acetonitrile) to yield 43 mg 3-(difluoromethoxy)-5-(methylsulfonyl)benzoic acid.

[0668] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ=13.9 (br s, 1H), 8.26 (s, 1H), 7.97 (s, 2H), 7.49 (t, J=73 Hz, 1H). (Signal of CH3-group is hidden under solvent signal)

[0669] ESI mass [m/z]: 267.0 [M+H].sup.+

Synthesis of N-{(1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}-3-(difluoromethoxy)-5-(methylsulfonyl)benzamide (example I-54)

Step 1: N-{(1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}-3-(difluoromethoxy)-5-(methylsulfanyl)benzamide

[0670] ##STR00077##

[0671] A solution of 80 mg (0.31 mmol) 3-(difluoromethoxy)-5-(methylsulfanyl)benzoic acid, 236 mg (0.62 mmol) HATU, 0.19 mL (1.1 mmol)N-ethyldiisopropylamine in 2 mL DMF was stirred for 60 min at room temperature. A solution of 80 mg 2-{5-[(1S)-1-aminoethyl]-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carbonitrile hydrochloride (1:1) in 1 mL DMF was then added and the mixture stirred overnight. The reaction mixture was diluted with 1 mL acetonitrile and purified directly by reversed phase chromatography (H.sub.2O/acetonitrile) to provide 122 mg N-{(1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}-3-(difluoromethoxy)-5-(methylsulfanyl)benzamide.

[0672] ESI mass [m/z]: 437.0 [M+H].sup.+

Step 2: N-{(1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}-3-(difluoromethoxy)-5-(methylsulfonyl)benzamide

[0673] ##STR00078##

[0674] To a solution of 120 mg (0.27 mmol)N-{(1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}-3-(difluoromethoxy)-5-(methylsulfanyl)benzamide dissolved in 5 mL CH.sub.2Cl.sub.2 were added 0.05 mL formic acid and 0.19 mL (1.92 mmol) of an aqeueous 30% hydrogen peroxide solution. The reaction mixture was stirred overnight at room temperature. It was then quenched by the addition of a 40% aqueous NaHSO.sub.3 solution to destroy excess hydrogen peroxide. Water was added and the mixture repeatedly extracted with ethyl acetate. The combined organic layers were dried with Na.sub.2SO.sub.4 and the solvents removed under reduced pressure to provide 108 mg N-{(1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}-3-(difluoromethoxy)-5-(methylsulfonyl)benzamide.

[0675] .sup.1H-NMR peak list (400 MHz, DMSO-d.sub.6): see table 1.

[0676] ESI mass [m/z]: 469.1 [M+H].sup.+

Synthesis of 3-(cyclopropylsulfanyl)-5-(difluoromethoxy)benzonitrile

[0677] ##STR00079##

[0678] To a solution of 0.90 g (4.8 mmol) 3-(difluoromethoxy)-5-fluorobenzonitrile (obtained from FCH Group) in 10 mL DMF at 0° C. were added 694 mg (7.21 mmol) sodium cyclopropanethiolate. The mixture was stirred for 1 h at 0° C. after which it was allowed to warm to room temperature. The reaction mixture was stirred overnight at room temperature. It was then directly purified by reversed-phase chromatography (H.sub.2O/acetonitrile) to yield 283 mg of the title compound.

[0679] ESI mass [m/z]: 242.0 [M+H].sup.+

[0680] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ=7.69 (s, 1H), 7.50 (s, 1H), 7.47 (s, 1H), 7.36 (t, J=73 Hz, 1H), 2.43-2.36 (m, 1H), 1.22-1.15 (m, 2H), 0.61-0.66 (m, 2H).

[0681] 3-(Cyclopropylsulfanyl)-5-(difluoromethoxy)benzonitrile was then further converted to 3-(cyclopropylsulfonyl)-5-(difluoromethoxy)benzoic acid (INT-14) via hydrolysis of the nitrile and oxidation of the thioether to the sulfone. These transformations were conducted in analogy to the conditions described above for the synthesis of 3-(difluoromethoxy)-5-(methylsulfonyl)benzoic acid (INT-9).

Synthesis of 3-bromo-5-(1-fluorocyclopropyl)benzoic acid (INT-10)

Step 1: methyl 3-formylbenzoate

[0682] ##STR00080##

[0683] 3-formylbenzoic acid (95 g, 633 mmol) was dissolved in acetonitrile (1000 mL) and CDI (123 g, 759 mmol) was added in portions at room temperature. The mixture was stirred at room temperature 30 min and methanol (60.8 g, 1898 mmol) was added in one portion. The mixture was refluxed overnight, then cooled to room temperature, and evaporated in vacuo at 45° C. The residue was dissolved in ethyl acetate (1000 mL), washed with 10% aq. solution of NaHSO.sub.4 (2×200 mL) and brine (1×100 mL), dried over Na.sub.2SO.sub.4, and evaporated in vacuo at 45° C. Crude methyl 3-formylbenzoate (97 g, 93% yield) as a colorless liquid was used in the next step without further purification.

Step 2: methyl 3-bromo-5-formylbenzoate

[0684] ##STR00081##

[0685] Methyl 3-formylbenzoate (97 g, 591 mmol) was dissolved in 96% sulfuric acid (1000 mL), the solution was cooled to 0° C. and N-Bromosuccinimide (121 g, 680 mmol) was added in portions. The mixture was stirred at room temperature overnight then poured into ice and extract with dichloromethane (3×500 mL). The combined organic layers were washed with 10% aq. solution of potassium carbonate (2×500 mL) and brine (1×100 mL), dried over Na.sub.2SO.sub.4, and evaporated in vacuo at 45° C. The crude product was recrystallized from MTBE (100 mL) to obtain 130 g of methyl 3-bromo-5-formylbenzoate (91% yield) as a white solid.

Step 3: methyl 3-bromo-5-vinylbenzoate

[0686] ##STR00082##

[0687] Methyltriphenylphosphanium iodide (249 g, 615 mmol) was suspended in THF (2500 mL) and the mixture was cooled to +5° C. Sodium tert-butoxide (68.4 g, 609 mmol) was then added in portions and the mixture was stirred at +5° C. for 30 min. Methyl 3-bromo-5-formylbenzoate (130 g, 535 mmol) in THF (500 mL) was added dropwise to the mixture at +5° C. and the mixture was stirred at room temperature overnight. Ethyl acetate (2500 mL) was added and the mixture was washed with brine (3×500 mL), dried over Na.sub.2SO.sub.4, and evaporated in vacuo at 45° C. The crude product was purified by column chromatography to obtain 49.9 g of methyl 3-bromo-5-vinylbenzoate (39% yield) as a yellow oil.

Step 4: methyl 3-bromo-5-(2-bromo-1-fluoroethyl)benzoate

[0688] ##STR00083##

[0689] Methyl 3-bromo-5-vinylbenzoate (44.9 g, 186 mmol) was dissolved in dichloromethane (450 mL) and the mixture was cooled to +5° C., triethylamine trihydrofluoride (90.1 g, 559 mmol) and N-Bromosuccinimide (34.8 g, 196 mmol) were added to the mixture in one portion and the mixture was stirred at room temperature overnight. The mixture was washed with 10% aq. solution of potassium carbonate (2×200 mL) and brine (1×100 mL), dried over Na.sub.2SO.sub.4, and evaporated in vacuo at 45° C. The crude methyl 3-bromo-5-(2-bromo-1-fluoroethyl)benzoate was used in the next step without further purification. Yield 60 g (95%), brown oil.

Step 5: tert-butyl 3-bromo-5-(1-fluorovinyl)benzoate

[0690] ##STR00084##

[0691] Potassium tert-butoxide (39.6 g, 353 mmol) was suspended in hexane (600 mL), the mixture was cooled to 0° C. and methyl 3-bromo-5-(2-bromo-1-fluoroethyl)benzoate (60 g, 176 mmol) in hexane (100 mL) was added dropwise to the mixture. The mixture was slowly heated up to room temperature and stirred at this temperature for 1 h. Ethyl acetate (300 mL) was added and the mixture was washed with brine (2×200 mL), dried over Na.sub.2SO.sub.4, and evaporated in vacuo at 45° C. The crude product was purified by distillation in vacuo to obtain 12.4 g of tert-butyl 3-bromo-5-(1-fluorovinyl)benzoate (23% yield) as a colorless liquid; bp 110-112° C./1 mmHg.

Step 6: tert-butyl 3-bromo-5-(1-fluorocyclopropyl)benzoate

[0692] ##STR00085##

[0693] To a well stirred mixture of tert-butyl 3-bromo-5-(1-fluorovinyl)benzoate (16.5 g, 40 mmol) in diethyl ether (125 mL) in a liquid nitrogen bath under inert atmosphere, was added catalytic Pd(OAc).sub.2. Excess of diazomethane in diethyl ether was added by the help of a dropping funnel. The reaction temperature was gradually raised to room temperature and the mixture stirred for 1 h. After the completion of the reaction, the solvent was evaporated under reduced pressure. The crude mass was then purified by column chromatography (dichloromethane/hexane 0-50%) to give 2.4 g of tert-butyl 3-bromo-5-(1-fluorocyclopropyl)benzoate in 19% yield as yellow oil.

Step 7: 3-bromo-5-(1-fluorocyclopropyl)benzoic acid (INT-10)

[0694] ##STR00086##

[0695] Tert-butyl 3-bromo-5-(1-fluorocyclopropyl)benzoate (2.4 g, 7.61 mmol) was dissolved in dichloromethane (11 mL) and trifluoroacetic acid (11 mL) was added. The mixture was stirred at room temperature for 2 h and evaporated in vacuo at 55° C. The crude product was recrystallized from acetonitrile (3 mL) to obtain 1.73 g 3-bromo-5-(1-fluorocyclopropyl)benzoic acid (88% yield) as a white solid.

[0696] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ=1.28 (m, 2H), 1.53 (m, 2H), 7.64 (s, 1H), 7.80 (s, 1H), 7.95 (s, 1H), 13.45 (s, 1H). Measured using a Bruker AVANCE DRX 500 MHz spectrometer.

[0697] ESI mass [m/z]: 256.9 [M−H].sup.−

Synthesis of 3-methylsulfonyl-5-(trifluoromethoxy)benzoic acid (INT-6)

[0698] ##STR00087##

[0699] A mixture of 2.95 g (17.5 mmol) trans-N,N-dimethylcyclohexane-1-2-diamine and 11.4 g (35 mmol) cesium carbonate in 60 mL DMF was degassed for 30 min by purging with argon. 5 g (17.5 mmol) 3-bromo-5-(trifluoromethoxy)benzoic acid, 3.58 g (35 mmol) sodium methanesulfinate and 3.34 g (17.5 mmol) copper(I) iodide were added and the mixture further purged with argon for 5 min. The mixture was stirred at 120° C. over night, cooled to room temperature and then three times extracted with dichloromethane. The aqueous layer was acidified to pH 2 using concentrated hydrochloric acid and again extracted with dichloromethane. The dichlormethane phase was washed with brine several times. The layers were separated, and the combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and filtered.

[0700] The solvent was removed under reduced pressure and the residue triturated with n-pentane, filtered-off and dried to provide 3.2 g of 3-methylsulfonyl-5-(trifluoromethoxy)benzoic acid.

[0701] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ=14.00 (br s, 1H, COOH), 8.42 (s, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 3.39 (s, 3H).

[0702] ESI mass [m/z]: 285.0 [M+H].sup.+

[0703] In a similar way, the following intermediates have been prepared: [0704] 3-(cyclopropylsulfonyl)-5-(trifluoromethoxy)benzoic acid (INT-16) [0705] 3-(ethylsulfonyl)-5-(trifluoromethoxy)benzoic acid (INT-17) [0706] 3-(isopropylsulfonyl)-5-(trifluoromethoxy)benzoic acid (INT-18)

Synthesis of 3-bromo-5-[(trifluoromethyl)sulfonyl]benzoic acid

Step 1: Synthesis of 3-bromo-5-sulfanylbenzonitrile

[0707] ##STR00088##

[0708] A solution of 3-bromo-5-fluorobenzonitrile (27 g, 135 mmol) and Na.sub.2S (12.64 g, 162 mmol) in dry DMF (250 mL) was stirred under argon at 35-40° C. for 22 h. The reaction mixture was poured into a 1N solution of NaOH (1 L). The emulsion was washed with DCM (2×350 mL), the aqueous layer was acidified with concentrated HCl (150 mL) and the resulting emulsion was extracted by diethyl ether (2×600 mL). The organic layer was separated, washed with brine (3×600 mL) and evaporated in vacuo to obtain 20 g (yield 69%) of 3-bromo-5-sulfanylbenzonitrile as a viscous yellowish oil. This crude material was used in the next step without purification.

[0709] .sup.1H NMR (400 MHz, CDCl.sub.3): δ=7.63 (t, J=1.7 Hz, 1H), 7.55 (t, J=1.6 Hz, 1H), 7.46 (t, J=1.5 Hz, 1H), 3.61 (s, 1H). Measured with a Varian Gemini 2000 NMR machine.

Step 2: Synthesis of 3-bromo-5-sulfamoylbenzoic acid

[0710] ##STR00089##

[0711] A solution of 3-bromo-5-sulfanylbenzonitrile (20 g, 93 mmol) and NaOH (37.4 g, 934 mmol) in water (155 mL) and methanol (225 mL) was stirred under reflux for 12 h. The reaction mixture was concentrated in vacuo and 150 mL of the residue were poured into diluted hydrochloric acid (15%, 20 mL). The precipitate was filtered off, washed with boiling water (3×100 mL) and crystallized from MeOH/water (2:1). The solution was kept in a freezer for 2 h, the precipitate was filtered off, washed with cold MeOH/water (1:1) and hexane and dried in vacuo to obtain 14.1 g of 3-bromo-5-sulfamoylbenzoic acid.

[0712] .sup.1H NMR (400 MHz, CDCl.sub.3): δ=8.01 (br s, 1H), 7.92 (br s, 1H), 7.65 (br s, 1H), 3.63 (s, 1H). Measured with a Varian Gemini 2000 NMR machine.

Step 3: Synthesis of 3-bromo-5-[(trifluoromethyl)sulfanyl]benzoic acid

[0713] ##STR00090##

[0714] A solution of 3-bromo-5-sulfanylbenzoic acid (14 g, 60 mmol) and TEA (18.23 g, 180 mmol) in DMF (250 mL) was cooled down to 5° C. (argon atmosphere) and ICF.sub.3 was bubbled through this solution at 5° C. until the weight was increased by 37 g. 1,1′-Dimethyl-4,4′-bipyridinium dichloride (Paraquat) (3.1 g, 12 mmol) was added and the reaction mixture was stirred at r.t. for 48 h. The reaction mixture was poured into a mixture of water and ice (1500 mL) and NaHCO.sub.3 (53 g). The precipitate was filtered off, the filtrate was washed with diethyl ether (2×400 mL) and the aqueous layer was acidified with concentrated HCl (50 mL). The emulsion was extracted with diethyl ether (2×400 mL), the organic layer was washed with water (2×400 mL), brine (2×400 mL) and evaporated in vacuo to give 16.2 g of crude 3-bromo-5-[(trifluoromethyl)sulfanyl]benzoic acid. This material was sublimed in vacuo (130° C./3.5 mbar to give 11.7 g (purity 90%) 3-bromo-5-[(trifluoromethyl)sulfanyl]benzoic acid which was used in the next step without further purification.

[0715] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ=13.76 (s, 1H), 8.24-8.20 (m, 2H), 8.15 (s, 1H), 8.40 (s, 1H). Measured with a Varian Gemini 2000 NMR machine.

[0716] .sup.19F NMR (376 MHz, DMSO-d.sub.6): δ=−41.23. Measured with a Varian Gemini 2000 NMR machine.

Step 4: Synthesis of 3-bromo-5-[(trifluoromethyl)sulfonyl]benzoic acid

[0717] ##STR00091##

[0718] A solution of H.sub.2O.sub.2 (40%, 6.5 mL) was added to a solution of 3-bromo-5-[(trifluoromethyl)sulfanyl]benzoic acid (5.42 g, 18 mmol) in AcOH (50 mL) at 55-65° C. and the reaction mixture was stirred at this temperature for 12 h. The addition of H.sub.2O.sub.2 was repeated (40%, 6.5 mL) and the reaction mixture was stirred at 55-65° C. for additional 24 h. H.sub.2O.sub.2 (40%, 6.5 mL) was added again and the reaction mixture was stirred at 70-75° C. for additional 24 h. The hot reaction mixture was diluted with water to 100 mL and cooled down to r.t. The precipitate was filtered off, washed with water and dried in vacuo to give 5 g (83% yield) of pure 3-bromo-5-[(trifluoromethyl)sulfonyl]benzoic acid.

[0719] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ=14.21 (br s, 1H), 8.60 (s, 1H), 8.58 (s, 1H), 8.40 (s, 1H). Measured with a Varian Gemini 2000 NMR machine.

[0720] .sup.19F NMR (376 MHz, DMSO-d.sub.6): δ=−78.80. Measured with a Varian Gemini 2000 NMR machine.

Synthesis of 3-cyclopropyl-5-[(trifluoromethyl)sulfonyl]benzoic acid (INT-13)

Step 1: Synthesis of 3-cyclopropyl-5-[(trifluoromethyl)sulfanyl]benzoic acid

[0721] ##STR00092##

[0722] (Ph.sub.3P).sub.2PdCl.sub.2 (0.663 g, 0.945 mmol) was added to a stirred solution of 3-bromo-5-[(trifluoromethyl)sulfanyl]benzoic acid (9.48 g, 31.5 mmol), cyclopropylboronic acid (8.12 g, 95 mmol), K.sub.3PO.sub.4 (20 g, 95 mmol) and Ph.sub.3P (0.496 g, 1.89 mmol) in diglyme (175 mL) at 75° C. under argon atmosphere. The reaction mixture was stirred at 95-100° C. for 12 h, then cooled down and poured into a 0.5 M solution of NaHCO.sub.3 (1000 mL). The precipitate was filtered off and the filtrate was washed with ethyl acetate (2×500 mL). The aqueous layer was separated and acidified with concentrated HCl (150 mL). The precipitate was filtered off, washed with hot water and dried in vacuo (1 torr, 100° C., 3 h) to obtain 6.55 g (79% yield) of 3-cyclopropyl-5-[(trifluoromethyl)sulfanyl]benzoic acid which was used in the next step without further purification.

[0723] .sup.1H NMR (400 MHz, CDCl.sub.3): δ=8.16 (t, J=1.6 Hz, 1H), 7.89 (t, J=1.7 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 2.00 (tt, J=8.5, 5.0 Hz, 1H), 1.16-1.01 (m, 2H), 0.80 (dt, J=6.9, 4.9 Hz, 2H). Measured with a Varian Gemini 2000 NMR machine.

[0724] .sup.19F NMR (376 MHz, CDCl.sub.3): δ=−45.53. Measured with a Varian Gemini 2000 NMR machine.

Step 2: Synthesis 3-cyclopropyl-5-[(trifluoromethyl)sulfonyl]benzoic acid

[0725] ##STR00093##

[0726] A solution of H.sub.2O.sub.2 (40%, 9 mL) was added to a solution of 3-cyclopropyl-5-[(trifluoromethyl)sulfanyl]benzoic acid (6.03 g, 23 mmol) in AcOH (50 mL) at 55-65° C. and the reaction mixture was stirred at this temperature for 4 h. The addition of H.sub.2O.sub.2 was repeated (40%, 9 mL) and the reaction mixture was stirred at 55-65° C. for additional 48 h. H.sub.2O.sub.2 (40%, 9 mL) was added again and the reaction mixture was stirred at 55-65° C. for additional 12 h. The reaction was not complete. Water (200 mL) was added to the reaction mixture and the precipitate was filtered off. It was then dissolved in hot (ca 70° C.) AcOH (25 mL) and the solution was filtered off through a sintered glass filter. A solution of H.sub.2O.sub.2 (40%, 9 mL) was added to the filtrate and the reaction mixture was stirred at 55-65° C. for additional 12 h. The reaction mixture was diluted with water (50 mL) and the solution was kept in a freezer for 2 h. The precipitate was filtered off, washed with water and dried in vacuo (1 torr, 100° C., 3 h) to obtain 4 g (yield 59%) of the title compound as a white solid.

[0727] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ=13.82 (br s, 1H), 8.22 (d, J=1.6 Hz, 1H), 8.13-8.03 (m, 2H), 2.36-2.28 (m, 1H), 1.21-1.03 (m, 2H), 0.88 (dt, J=6.9, 4.7 Hz, 2H). Measured with a Varian Gemini 2000 NMR machine.

[0728] .sup.19F NMR (376 MHz, DMSO-d.sub.6): δ=−78.30. Measured with a Varian Gemini 2000 NMR machine.

[0729] ESI mass [m/z]: 295.0 [M+H].sup.+

Synthesis of 3-bromo-5-(1-fluorocyclopropyl)benzoic acid (INT-11)

Step 1: 1,3-dibromo-5-(1,1-difluoroethyl)benzene

[0730] ##STR00094##

[0731] 1-(3,5-dibromophenyl)ethanone (15.0 g, 54.0 mmol, 1.00 eq) was added to Bis(2-methoxyethyl)aminosulfur trifluoride (60.6 g, 274 mmol, 60.0 mL, 5.08 eq) at 25-30° C. The mixture was stirred at 40° C. for 12 h. The mixture was then diluted with CH.sub.2Cl.sub.2 (50 mL) and quenched by water (50 mL). The mixture was separated and the aqueous phase was extracted with EtOAc (3×20 mL). The combined organic layer was concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether) to afford 1,3-dibromo-5-(1,1-difluoroethyl)benzene (14.2 g, 47.3 mmol, 87.7% yield) as a colorless oil.

Step 2: 1-bromo-3-(1,1-difluoroethyl)-5-vinylbenzene

[0732] ##STR00095##

[0733] Pd(dppf)Cl.sub.2 (3.16 g, 4.32 mmol, 0.08 eq) was added to a mixture of 1,3-dibromo-5-(1,1-difluoroethyl)benzene (15.8 g, 52.7 mmol, 1.00 eq), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (7.30 g, 47.4 mmol, 0.90 eq) and Na.sub.2CO.sub.3 (11.2 g, 105 mmol, 2.00 eq) in dioxane (80.0 mL) and water (20.0 mL) at 25-30° C. under N.sub.2. The mixture was stirred at 80° C. for 12 h under N.sub.2. The mixture was concentrated to remove the solvent. The residue was diluted with EtOAc (100 mL) and water (100 mL). The mixture was separated. The aqueous phase was extracted with EtOAc (50 mL×3). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated to give the crude product. The product was purified by silica gel chromatography (petroleum ether) to afford 1-bromo-3-(1,1-difluoroethyl)-5-vinylbenzene (9.90 g, 40.1 mmol, 76.1% yield) as a colorless oil.

Step 3: 3-bromo-5-(1,1-difluoroethyl)benzoic acid (INT-11)

[0734] ##STR00096##

[0735] KMnO.sub.4 (3.17 g, 20.0 mmol, 0.50 eq) was added to a mixture of 1-bromo-3-(1,1-difluoroethyl)-5-vinylbenzene (9.90 g, 40.07 mmol, 1.00 eq) and NaIO.sub.4 (34.3 g, 160 mmol, 8.88 mL, 4.00 eq) in acetone (100 mL) and H.sub.2O (60.0 mL) at 25-30° C. The mixture was stirred at 25-30° C. for 0.5 h. The mixture was diluted with EtOAc (100 mL) and water (100 mL). The mixture was filtered and the filter cake was washed with EtOAc/H.sub.2O (1/1, 50 mL×2). The layers of the combined filtrate were separated. The aqueous phase was acidified to pH=2-3 by hydrochlorid acid (2 N) and extracted with EtOAc (100 mL×3). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated to give the crude product. The product was purified by reversed phase chromatography (TFA, MeCN/H.sub.2O) to give 3-bromo-5-(1,1-difluoroethyl)benzoic acid (3.10 g, 11.40 mmol, 28.5% yield, 97.5% purity) as a white solid.

[0736] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ=13.60 (br s, 1H), 8.14 (s, 1H), 8.02 (d, J=2.4 Hz, 2H), 2.00 (t, J=19.2 Hz, 3H). Measured on a Varian S 400 MHz NMR.

[0737] ESI mass [m/z]: 262.9 [M−H].sup.−

Synthesis of 3-bromo-5-(2,2-difluorocyclopropyl)benzoic acid (INT-12)

Step 1: 3-bromo-5-vinylbenzonitrile

[0738] ##STR00097##

[0739] [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl.sub.2dppf) (1.65 g, 2.22 mmol) was added to a refluxing solution (Ar atmosphere) of 3,5-dibromobenzonitrile (29 g, 111 mmol), potassium vinyltrifluoroborate (18.59 g, 139 mmol), Et.sub.3N (28.1 g, 38.7 ml, 278 mmol) and p-methoxyphenol (2 mg) in iso-propanol (750 mL). The reaction mixture was stirred under reflux for 24 h. GCMS analysis of the reaction mixture showed incomplete conversion, therefore potassium vinyltrifluoroborate (1.5 g) and PdCl.sub.2dppf (425 mg) were added to the reaction mixture which was then stirred under reflux for additional 4 h. After cooling down to room temperature the reaction mixture was evaporated in vacuo, and triturated with diethylether (750 mL) and water (750 mL). The organic layer was separated, filtered off, washed with brine (800 mL), separated and evaporated in vacuo to give 20 g of an oil containing (according to GCMS) 78% of 3-bromo-5-vinylbenzonitrile and 22% of 3,5-divinylbenzonitrile. This mixture was used in the next step.

[0740] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.75 (d, J=1.8 Hz, 1H), 7.66 (d, J=1.7 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 6.63 (dd, J=17.6, 10.9 Hz, 1H), 5.88-5.79 (m, 1H), 5.46 (d, J=10.9 Hz, 1H). Measured using a Varian Gemini 2000 spectrometer.

Step 2: 3-bromo-5-(2,2-difluorocyclopropyl)benzonitrile

[0741] ##STR00098##

[0742] Sodium bromo(difluoro)acetate (56 g) was added in portions (over 20-15 min) to a solution of the crude product obtained in the previous step (11.44 g) in diglyme (25 mL) at 70-75° C. After cooling down to room temperature, the reaction mixture was poured into water (600 mL) and the emulsion formed was extracted with diethylether (600 mL). The black tar was filtered off, the organic layer was separated, washed with brine (600 mL) and dried over MgSO.sub.4. After filtration the filtrate was evaporated and dried in vacuo to give 17 g of a dark oil that contained 76% of 3-bromo-5-(2,2-difluorocyclopropyl)benzonitrile and 24% of 3,5-bis(2,2-difluorocyclopropyl)benzonitrile. Preparative flash column chromatography (hexane/EtOAc) afforded 6.9 g of pure 3-bromo-5-(2,2-difluorocyclopropyl)benzonitrile.

[0743] .sup.1H NMR (400 MHz, CDCl.sub.3): δ=7.70 (t, J=1.6 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 2.75 (td, J=12.0, 8.0 Hz, 1H), 1.95 (tdd, J=11.7, 8.2, 5.3 Hz, 1H), 1.66 (dtd, J=12.2, 8.2, 3.9 Hz, 1H). Measured using a Varian Gemini 2000 spectrometer.

Step 3: 3-bromo-5-(2,2-difluorocyclopropyl)benzoic acid (INT-12)

[0744] ##STR00099##

[0745] A solution of 3-bromo-5-(2,2-difluorocyclopropyl)benzonitrile (3.87 g, 15 mmol) and sodium hydroxide (4.2 g, 105 mmol) in iso-propanol (60 mL) and water (25 mL) was stirred under reflux for 12 h. The reaction mixture was concentrated to 30-40 mL and the concentrate was added in portions to diluted HCl (10%, 200 mL). The precipitate formed was filtered off, washed with water and hexane and dried in vacuo (1 torr, 60° C.) for 3 h to obtain 3.74 g (90%) 3-bromo-5-(2,2-difluorocyclopropyl)benzoic acid as a white solid.

[0746] ESI mass [m/z]: 278.9 [M+H].sup.+

[0747] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ=13.4 (br s, 1H), 7.94 (s, 1H), 7.83 (s, 1H), 7.77 (s, 1H), 3.22-3.12 (m, 1H), 2.20-1.90 (m, 2H).

Synthesis of 3-chloro-N-{(1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-3-cyclopropyl-1H-1,2,4-triazol-5-yl]ethyl}-5-(methylsulfonyl)benzamide (example I-40)

Step 1: 2-{3-cyclopropyl-5-[(1S)-1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carbonitrile

[0748] ##STR00100##

[0749] A solution of 5.00 g (95% purity, 21.6 mmol) (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoic acid and 0.08 mL (1 mmol) DMF in 30 mL absolute CH.sub.2Cl.sub.2 was treated with 3.78 mL (43.3 mmol) oxalyl chloride at 0° C. The reaction mixture was stirred overnight at ambient temperature. All volatiles were removed under reduced pressure and the residue used for the next step without further purification.

[0750] To a solution of 3.23 g (21.6 mmol) ethyl cyclopropanecarboximidate hydrochloride (1:1) in 40 mL absolute THF were added at 0° C. 15.1 mL (86.4 mmol) absolute DIPEA. The acid chloride prepared in the first step was dissolved in 20 mL absolute THF and added dropwise within 20 min to the solution of the imidate. After 30 min stirring at 0° C. 3.47 g (23.7 mmol) 2-hydrazino-1,3-thiazole-5-carbonitrile and 10 mL absolute THF were added. The reaction mixture was stirred for 30 min at 0° C. and overnight at ambient temperature. Further 630 mg (4.49 mmol) 2-hydrazino-1,3-thiazole-5-carbonitrile were added and stirring at room temperature was continued overnight. Then another portion, 424 mg (3.02 mmol) of 2-hydrazino-1,3-thiazole-5-carbonitrile was added and stirring continued for 3 d. All volatiles were removed under reduced pressure. To the residue was added 250 mL water and the mixture was extracted with 250 mL EtOAc. The phases were separated and the aqueous phase extracted several times with EtOAc. The combined organic phases were washed with brine and dried over Na.sub.2SO.sub.4. The solvent was removed under reduced pressure and the residue purified by chromatography on silica (cyclohexane/ethyl acetate) to provide 1.16 g of 2-{3-cyclopropyl-5-[(1S)-1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carbonitrile.

[0751] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ=8.35 (s, 1H), 7.84 (s, 4H), 5.91 (q, J=6.8 Hz, 1H), 2.15-2.05 (m, 1H), 1.78 (d, J=6.8 Hz, 3H), 1.10-1.00 (m, 2H), 0.95-0.85 (m, 2H).

[0752] ESI mass [m/z]: 391.1 [M+H]

Step 2: 2-{5-[(1S)-1-aminoethyl]-3-cyclopropyl-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carbonitrile (INT-7)

[0753] ##STR00101##

[0754] A solution of 100 mg (0.25 mmol) 2-{3-cyclopropyl-5-[(1S)-1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carbonitrile and 0.02 mL hydrazine hydrate in 2 mL ethanol was heated for 2 h 10 min at 40° C. The conversion of the starting material was closely monitored by HPLC as prolonged heating results in degradation of the desired product. The resulting suspension was stirred for 1 h at ambient temperature. Then 3 mL ethanol was added and the suspension cooled to 5-10° C. The mixture was filtered and the residue washed with ice-cold ethanol. The filtrate was concentrated under reduced pressure to yield 83 mg (max. 60% pure) of 2-{5-[(1S)-1-aminoethyl]-3-cyclopropyl-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carbonitrile.

[0755] ESI mass [m/z]: 261.1 [M+H].sup.+

Step 3: 3-chloro-N-{(1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-3-cyclopropyl-1H-1,2,4-triazol-5-yl]ethyl}-5-(methylsulfonyl)benzamide

[0756] ##STR00102##

[0757] A solution of 81 mg (0.34 mmol) 3-chloro-5-(methylsulfonyl)benzoic acid, 239 mg (0.63 mmol) HATU, 0.19 mL (1.1 mmol)N-ethyldiisopropylamine in 2 mL DMF was stirred for 60 min at room temperature. A solution of 82 mg of the crude product obtained in step 2 in 1 mL DMF was then added and the mixture stirred over night. The reaction mixture was then purified directly by reversed phase chromatography (H.sub.2O/acetonitrile) to provide 42 mg 3-chloro-N-{(1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-3-cyclopropyl-1H-1,2,4-triazol-5-yl]ethyl}-5-(methylsulfonyl)benzamide.

[0758] .sup.1H-NMR peak list (400 MHz, DMSO-d.sub.6): see table 1.

[0759] ESI mass [m/z]: 477.0 [M+H].sup.+

Synthesis of (rac)-3-(1-cyanocyclopropyl)-N-{1-[1-(5-cyano-1,3-thiazol-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}-5-(trifluoromethoxy)benzamide (example I-87)

Step 1: 3-(cyanomethyl)-5-(trifluoromethoxy)benzoic acid

[0760] ##STR00103##

[0761] A solution of potassium fluoride (153 mg, 2.63 mmol) in water (2.5 mL) was added to a mixture of 3-bromo-5-(trifluoromethoxy)benzoic acid (250 mg, 0.88 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (97.5 mg, 1.05 mmol) in DMSO (8.0 mL) and the resulting mixture was degassed. Then, 1,1-bis(diphenylphosphino)ferrocenedichloropalladium(II) (64.1 mg, 0.088 mmol) was added and the reaction mixture was heated to 130° C. for 16 h. A second batch of the reaction was conducted under identical conditions. After cooling to room temperature, both reaction mixtures were combined and filtered over Celite. The filter cake was washed with ethyl acetate. The combined filtrates were brought to pH 8-9 by addition of 1.0 M aqueous sodium hydroxide solution. The layers were separated, the aqueous layer was acidified by addition of 1.0 M hydrochloric acid and extracted with ethyl acetate. The basic and the acidic extracts contained the desired product. Hence, all organic layers were combined, dried over sodium sulfate and concentrated to dryness. The residue was purified by preparative HPLC to afford the title compound (217 mg, 50% of theory).

[0762] ESI mass [n/z]: 246.0 [M+H].sup.+

[0763] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=13.6 (br s, 1H), 7.99 (s, 1H), 7.77 (s, 1H), 7.66 (s, 1H), 4.23 (s, 2H).

Step 2: 3-(1-cyanocyclopropyl)-5-(trifluoromethoxy)benzoic acid (INT-21)

[0764] ##STR00104##

[0765] A mixture of sodium hydride (65.3 mg, 63% dispersion in mineral oil, 1.71 mmol) and 1,2-dibromoethane (215 mg, 1.14 mmol) in DMF (1.0 mL) was cooled to 0° C. Then, a solution of 3-(cyanomethyl)-5-(trifluoromethoxy)benzoic acid (70.0 mg, 0.29 mmol) in DMF (1.0 mL) was slowly added dropwise at this temperature. After complete addition, the mixture was allowed to warm to room temperature and stirred overnight. Water was added and the pH was adjusted to 1 by addition of 1.0 M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated to dryness to afford the title compound which was used in the next step without further purification.

[0766] ESI mass [n/z]: 270.0 [M−H].sup.−

[0767] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=13.7 (br s, 1H), 7.99-7.96 (m, 1H), 7.84-7.66 (m, 1H), 7.53-7.50 (m, 1H), 1.90-1.81 (m, 2H), 1.73-1.64 (m, 2H).

Step 3: (rac)-3-(1-cyanocyclopropyl)-N-{1-[1-(5-cyano-1,3-thiazol-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}-5-(trifluoromethoxy)benzamide (example I-87)

[0768] ##STR00105##

[0769] A mixture of 2-[5-(1-aminoethyl)-1H-1,2,4-triazol-1-yl]-1,3-thiazole-5-carbonitrile hydrochloride (1:1) (60.0 mg, 234 μmol) and N,N-diisopropylethylamine (103 μL, 608 μmol) in DMF (1.0 mL) was stirred at room temperature. In a separate vial, a mixture of 3-(1-cyanocyclopropyl)-5-(trifluoromethoxy)benzoic acid (63.4 mg, 234 μmol) and HATU (155 mg, 409 μmol) in DMF was stirred at room temperature. After 1 h, the two mixtures were combined and stirring was continued overnight at room temperature. The reaction mixture was directly purified by preparative HPLC to afford the title compound (60.1 mg, 54% of theory).

[0770] ESI mass [m/z]: 474.1 [M+H].sup.+

[0771] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=9.43 (d, 1H), 8.67 (s, 1H), 8.32 (s, 1H), 7.88-7.83 (m, 1H), 7.79-7.74 (m, 1H), 7.49 (s, 1H), 6.08-6.00 (m, 1H), 1.90-1.79 (m, 2H), 1.71-1.61 (m, 5H).

Synthesis of 3-[bromo(difluoro)methyl]-5-chlorobenzoic acid (INT-22)

Step 1: methyl 3-chloro-5-methylbenzoate

[0772] ##STR00106##

[0773] Sulfuric acid (1.00 g) was added to a suspension of 3-chloro-5-methylbenzoic acid (10.20 g, 59.8 mmol) in methanol (80 mL). The reaction mixture was refluxed for 12 h. The solvent was evaporated and dichloromethane (80 mL) was added to the residue. The mixture was washed with water (60 mL). The organic phase was dried over Na.sub.2SO.sub.4. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure to give methyl 3-chloro-5-methylbenzoate as a yellow oily liquid (10.55 g). Yield: 96%.

[0774] .sup.1H-NMR (CDCl.sub.3): δ=7.81 (m, 1H), 7.73 (m, 1H), 7.35 (m, 1H), 3.91 (s, 3H), 2.38 (s, 3H).

Step 2: methyl 3-chloro-5-(dibromomethyl)benzoate

[0775] ##STR00107##

[0776] N-bromosuccinimide (17.82 g, 100.1 mmol) and benzoyl peroxide (0.49 g, 2.0 mmol) were added to a solution of methyl 3-chloro-5-methylbenzoate (8.40 g, 45.5 mmol) in carbon tetrachloride (150 mL). The reaction mixture was refluxed for 48 h. Then N-bromosuccinimide (1.25 g, 7.0 mmol) and benzoyl peroxide (0.25 g, 1.0 mmol) were added, and the reaction mixture was refluxed for 24 h. After cooling, the precipitate was filtered off, and the filtrate was washed with a saturated aqueous solution of NaHCO.sub.3 (100 mL). The organic phase was dried over Na.sub.2SO.sub.4. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The mass of the crude product was 16.75 g. The purity was 67% according to .sup.1H NMR data. It was used in the next step without further purification.

[0777] .sup.1H-NMR (CDCl.sub.3): δ=8.07 (m, 1H), 7.9 (m, 1H), 7.78 (m, 1H), 6.6 (s, 1H), 3.9 (m, 3H).

Step 3: methyl 3-chloro-5-formylbenzoate

[0778] ##STR00108##

[0779] Concentrated sulfuric acid (98%) (55 mL) was added to methyl 3-chloro-5-(dibromomethyl)benzoate (13.50 g, 39.4 mmol) with stirring. The reaction mixture was stirred at 50° C. for 2 h. Then it was poured portionwise onto crashed ice (200 g). The mixture was extracted with ethyl acetate (2×150 mL). The combined organic phases were washed with saturated aqueous solution of NaHCO.sub.3 (150 mL). The organic phase was dried over Na.sub.2SO.sub.4. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. Mass of the crude product was 6.03 g which was used in the next step without further purification.

[0780] .sup.1H-NMR (CDCl.sub.3): δ=10.03 (s, 1H), 8.4 (m, 1H), 8.2 (m, 1H), 8.0 (m, 1H), 3.9 (m, 3H).

Step 4: methyl 3-chloro-5-(difluoromethyl)benzoate

[0781] ##STR00109##

[0782] A solution of morpholinosulfur trifluoride (11.04 g, 63.0 mmol) in dry CH.sub.2Cl.sub.2 (30 mL) was added dropwise at 0° C. (crashed ice/water bath) to a solution of methyl 3-chloro-5-formylbenzoate (7.00 g, 35.2 mmol) in dry CH.sub.2Cl.sub.2 (70 mL). The reaction mixture was stirred at 0° C. for 30 min, warmed up to room temperature and stirred for 20 h. The mixture was poured in small portions with stirring into the saturated aqueous solution of NaHCO.sub.3 (100 mL). Two phases were separated; the organic phase was washed with water (50 mL) and dried over Na.sub.2SO.sub.4. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. Mass of the crude product was 7.20 g. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate, 95:5) to give methyl 3-chloro-5-(difluoromethyl)benzoate as a colorless solid (5.04 g).

[0783] .sup.19F-NMR (CDCl.sub.3, referenced to C.sub.6F.sub.6 at −162.9): δ=113 (d, 2F).

[0784] .sup.1H-NMR (CDCl.sub.3): δ=8.1 (m, 1H), 8.0 (m, 1H), 7.7 (m, 1H), 6.55 (t, 1H), 3.9 (s, 3H).

Step 5: methyl 3-(bromodifluoromethyl)-5-chlorobenzoate

[0785] ##STR00110##

[0786] N-bromosuccinimide (2.85 g, 16.0 mmol) and benzoyl peroxide (0.10 g, 0.4 mmol) were added to a solution of methyl 3-chloro-5-(difluoromethyl)benzoate (2.40 g, 10.9 mmol) in carbon tetrachloride (25 mL) in a reaction flask equipped with a reflux condenser and a magnetic stirrer. The magnetically stirred mixture was exposed to a sunlamp for 23 h. Then N-bromosuccinimide (1.94 g, 10.9 mmol) and benzoyl peroxide (0.10 g, 0.4 mmol) were added, and the reaction mixture was exposed to a sunlamp for 23 h. Then N-bromosuccinimide (0.98 g, 5.5 mmol) and benzoyl peroxide (0.10 g, 0.4 mmol) were added, and the reaction mixture was exposed to a sunlamp for 9 h. After cooling, the precipitate was filtered off, and the filtrate was washed with a saturated aqueous solution of NaHCO.sub.3 (20 mL). The organic phase was dried over Na.sub.2SO.sub.4. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The mass of the crude product was 3.38 g. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate, 95:5) to give a mixture of methyl 3-(bromodifluoromethyl)-5-chlorobenzoate and bromomethyl 3-(bromodifluoromethyl)-5-chlorobenzoate in a ratio of 72:28 (2.31 g). The obtained mixture of two compounds was used directly in the next step.

[0787] .sup.19F-NMR (CDCl.sub.3, referenced to C.sub.6F6 at −162.9): δ=46.4, 46.7 (2 signals as singulett: 2F target compound and 2F impurity).

Step 6: 3-(bromodifluoromethyl)-5-chlorobenzoic acid (INT-22)

[0788] ##STR00111##

[0789] A solution of LiOH.H.sub.2O (0.94 g, 22.4 mmol) in water (15 mL) was added to a solution of a mixture (2.25 g) of methyl 3-(bromodifluoromethyl)-5-chlorobenzoate and bromomethyl 3-(bromodifluoromethyl)-5-chlorobenzoate in THF (20 mL). The mixture was stirred at room temperature for 20 h. Then it was acidified by the addition of concentrated hydrochloric acid and partitioned between ethyl acetate (40 mL) and water (20 mL). The aqueous phase was extracted with ethyl acetate (2×40 mL). The combined organic fractions were dried over Na.sub.2SO.sub.4. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure to give the product (2.30 g). It was dried under vacuum (0.08 mmHg) in an oil bath (temperature of the bath was 45° C.) for 3 h. 3-(Bromodifluoromethyl)-5-chlorobenzoic acid was obtained as a yellowish solid (2.10 g). The overall yield of the two steps was 68%.

[0790] .sup.19F-NMR (CDCl.sub.3, referenced to C.sub.6F6 at −162.9): δ=46.58 (s, 2F).

[0791] .sup.1H-NMR (CDCl.sub.3): δ=10.1 (br, 1H), 8.2 (m, 1H), 8.2 (m, 1H), 7.83 (m, 1H).

Synthesis of 3-chloro-5-[chloro(difluoro)methyl]benzoic acid (INT-23)

Step 1: dichloromethyl 3-chloro-5-(chlorodifluoromethyl)benzoate

[0792] ##STR00112##

[0793] N-chlorosuccinimide (7.88 g, 59.0 mmol) and benzoyl peroxide (0.12 g, 0.5 mmol) were added to a solution of 3-chloro-5-(difluoromethyl)benzoate (2.60 g, 11.8 mmol) in carbon tetrachloride (40 mL) in a reaction flask equipped with a reflux condenser and a magnetic stirrer. The magnetically stirred mixture was exposed to a sunlamp for 8 h. Then N-chlorosuccinimide (1.58 g, 11.8 mmol) and benzoyl peroxide (0.07 g, 0.3 mmol) were added, and the reaction mixture was exposed to a sunlamp for 27 h. Then N-chlorosuccinimide (1.58 g, 11.8 mmol) and benzoyl peroxide (0.07 g, 0.3 mmol) were added, and the reaction mixture was exposed to a sunlamp for 21 h. After cooling, the precipitate was filtered off, and the filtrate was washed with saturated aqueous solution of NaHCO.sub.3 (20 mL). The organic phase was dried over Na.sub.2SO.sub.4. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The mass of the crude product was 3.80 g. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate, 95:5) to give dichloromethyl 3-chloro-5-(chlorodifluoromethyl)benzoate (2.70 g).

[0794] .sup.19F-NMR (CDCl.sub.3, referenced to C.sub.6F6 at −162.9) δ=51.30 (s, 2F)

[0795] .sup.1H-NMR (CDCl.sub.3): δ=8.2 (m, 2H), 8.0 (m, 1H), 7.9 (m, 1H).

Step 2: 3-chloro-5-(chlorodifluoromethyl)benzoic acid (INT-23)

[0796] ##STR00113##

[0797] A solution of LiOH.H.sub.2O (1.22 g, 29.1 mmol) in water (15 mL) was added to a solution of dichloromethyl 3-chloro-5-(chlorodifluoromethyl)benzoate (2.70 g, 8.3 mmol) in THF (20 mL). The mixture was stirred at room temperature for 20 h. Then it was acidified by the addition of concentrated hydrochloric acid and partitioned between ethyl acetate (40 mL) and water (20 mL). The aqueous phase was extracted with ethyl acetate (2×40 mL). The combined organic fractions were dried over Na.sub.2SO.sub.4. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure to give the product (1.90 g). It was dried under vacuum (0.08 mmHg) in an oil bath (temperature of the bath was 45° C.) for 2 h. 3-(Bromodifluoromethyl)-5-chlorobenzoic acid was obtained as a yellow solid (1.77 g). The purity was 91% according to .sup.1H NMR data. The overall yield of the two steps was 62%.

[0798] .sup.19F-NMR (CDCl.sub.3, referenced to C.sub.6F6 at −162.9) δ=51.09 (s, 2F).

[0799] .sup.1H-NMR (CDCl.sub.3): δ=10.5 (br, 1H), 8.2 (m, 2H), 7.8 (m, 1H).

Synthesis of 3-bromo-5-(2-fluoropropan-2-yl)benzoic acid (INT-24)

Step 1: tert-butyl 3,5-dibromobenzoate

[0800] ##STR00114##

[0801] To a solution of compound 3,5-dibromobenzoic acid (23.1 g, 82.5 mmol) in dichloromethane (230 mL) were added DMAP (5 g, 41 mmol) and tert-butanol (15.3 g, 206 mmol). To the ice cooled mixture were added in portions 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide (EDC) hydrochloride (17.4 g, 90.8 mmol) and the reaction mixture was stirred overnight at room temperature. Water was added and the layers separated. The separated organic layer was washed with a 10% aqueous solution of NaHSO.sub.4, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to obtain 23.9 g of compound tert-butyl 3,5-dibromobenzoate.

Step 2: tert-butyl 3-bromo-5-(2-hydroxypropan-2-yl)benzoate

[0802] ##STR00115##

[0803] To a solution of tert-butyl 3,5-dibromobenzoate (23.9 g, 71.1 mmol) in dry THF (240 mL) were added at −78° C. dropwise a 2.5 M n-butyl lithium solution in hexanes (28.5 mL, 71.1 mmol) and acetone (8.3 g, 0.14 mol) sequentially. The reaction mixture was stirred overnight at room temperature, diluted with a saturated solution of NH.sub.4Cl (200 mL), and extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure. Purification of the residue via column chromatography on silica gel afforded 10.1 g of tert-butyl 3-bromo-5-(2-hydroxypropan-2-yl)benzoate (45% yield).

Step 3: tert-butyl 3-bromo-5-(2-fluoropropan-2-yl)benzoate

[0804] ##STR00116##

[0805] To a solution of tert-butyl 3-bromo-5-(2-hydroxypropan-2-yl)benzoate (10.1 g, 32.0 mmol) in dry dichloromethane (150 mL) was added at −20° C. dropwise a solution of morpholinosulfur trifluoride (6.7 g, 38.4 mmol) in dichloromethane (50 mL). The reaction mixture was stirred overnight at room temperature and then a saturated solution of NaHCO.sub.3 (100 mL) was added dropwise. The organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure. Purification of the residue via column chromatography on silica gel afforded 5.6 g of tert-butyl 3-bromo-5-(2-fluoropropan-2-yl)benzoate (55% yield).

Step 4: 3-bromo-5-(2-fluoropropan-2-yl)benzoic acid (INT-24)

[0806] ##STR00117##

[0807] To a solution of tert-butyl 3-bromo-5-(2-fluoropropan-2-yl)benzoate (5.6 g, 18 mmol) in methanol (56 mL) was added LiOH (4.2 g, 0.18 mmol) and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated, the residue was dissolved in water (50 mL) and then acidified with 2 M HCl. The organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford 3.7 g of 3-bromo-5-(2-fluoropropan-2-yl)benzoic acid (80% yield).

[0808] ESI mass [m/z]: 259.0 [M−H].sup.−

[0809] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=8.19 (s, 1H), 8.03 (s, 1H), 7.83 (s, 1H), 1.75 (d, J=20 Hz, 6H).

Synthesis of 3-(difluoromethoxy)-5-(trifluoromethoxy)benzoic acid (INT-25)

Step 1: 3-hydroxy-5-(trifluoromethoxy)benzoic acid

[0810] ##STR00118##

[0811] 3-bromo-5-(trifluoromethoxy)benzoic acid (20.0 g, 70.2 mmol) and tris(dibenzylideneacetone)dipalladium (Pd.sub.2(dba).sub.3) (1.29 g, 1.40 mmol) in dioxane (60 mL) and H.sub.2O (60 mL) was degassed for 5 minutes prior to the addition of NaOH (11.2 g, 281 mmol) and di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (tert-butyl XPhos) (1.49 g, 3.51 mmol). The mixture was degassed for a further 2 minutes and then heated under a nitrogen atmosphere at 100° C. for 3 hours. The mixture was concentrated. Water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (3×20 mL) to remove insoluble impurities. The aqueous phase was acidified by addition of 2 M HCl until pH=2. The mixture was extracted with CH.sub.2Cl2/MeOH (5/1) (3×50 mL). The combined organic layers were dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated. 3-hydroxy-5-(trifluoromethoxy)benzoic acid (14.0 g, 90% yield) was obtained as a yellow solid.

[0812] ESI mass [m/z]: 221.0 [M−H].sup.−

Step 2: 3-(difluoromethoxy)-5-(trifluoromethoxy)benzoic acid (INT-25)

[0813] ##STR00119##

[0814] The reaction was carried out in three batches in parallel. To a mixture of 3-hydroxy-5-(trifluoromethoxy)benzoic acid (4.00 g, 18.0 mmol) and KOH (4.55 g, 81.0 mmol) in CH.sub.2Cl.sub.2 (35 mL) and H.sub.2O (14 mL) was added [bromo(difluoro)methyl]-trimethyl-silane (9.14 g, 45.0 mmol). The reaction mixture exuded heat and gas evolved. The mixture was stirred at 25° C. for 16 hours. The mixture was acidified by addition of 2 M HCl until pH=1-2. The mixture was filtered and the filtrate was extracted with CH.sub.2Cl.sub.2 (3×30 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by preparative HPLC (H.sub.2O/acetonitrile). The three batches yielded 3-(difluoromethoxy)-5-(trifluoromethoxy)benzoic acid (in total 5.10 g, 35% yield) as a white solid.

[0815] ESI mass [m/z]: 271.0 [M−H].sup.−

[0816] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=13.8 (br s, 1H), 7.71 (s, 2H), 7.58 (s, 1H), 7.45 (t, J=73 Hz, 1H).

Synthesis of 3-cyclopropyl-5-(1,1-difluoroethyl)benzoic acid (INT-26)

[0817] ##STR00120##

[0818] A mixture of 300 mg (1.13 mmol) 3-bromo-5-(1-fluorocyclopropyl)benzoic acid, 122 mg (1.41 mmol) cyclopropylboronic acid, 841 mg (3.96 mmol) K.sub.3PO.sub.4, 32 mg (0.11 mmol) tricyclohexylphosphine in 6 mL toluene and 0.3 mL H.sub.2O was degassed by purging with argon. 13 mg (58 μmol) palladium(II) acetate were added. The mixture was heated for 16 h at 100° C. Water was added and the mixture extracted with toluene. The aqueous layer was then acidified to pH 2-3 using 1 M hydrochloric acid. A precipitate formed which was separated by filtration, washed with water and then dissolved in ethyl acetate. All insoluble material was removed by filtration. The filtrate was then concentrated under reduced pressure to provide 226 mg of 3-cyclopropyl-5-(1,1-difluoroethyl)benzoic acid which was used for the synthesis of the example compounds without further purification.

[0819] ESI mass [m/z]: 227.1 [M−H]+.sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ=13.3 (br s, 1H), 7.83 (s, 1H), 7.71 (s, 1H), 7.50 (s, 1H), 2.15-2.05 (m, 1H), 1.98 (t, J=18.8 Hz, 3H), 1.06-1.00 (m, 2H), 0.80-0.74 (m, 2H).

Synthesis of 2-(3-cyclopropyl-5-{(1S)-1-[3-cyclopropyl-5-(trifluoromethoxy)benzamido]ethyl}-1H-1,2,4-triazol-1-yl)-N,N-dimethyl-1,3-thiazole-5-carboxamide (example I-157)

Step 1: ethyl cyclopropanecarboximidate hydrochloride

[0820] ##STR00121##

[0821] Cyclopropanecarbonitrile (10.0 g, 149 mmol, 11.0 mL, 1.00 eq) was dissolved in 4M HCl/dioxane (70.0 mL). EtOH (6.87 g, 149 mmol, 8.71 mL, 1.00 eq) was slowly added at 0° C. dropwise. The mixture was stirred at 25° C. for 16 h until TLC (petroleum ether/ethyl acetate=1/1) indicated that the starting material was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to give crude product. The crude product was triturated with MTBE (50.0 mL) at 25° C. for 30 min. Ethyl cyclopropanecarboximidate hydrochloride (20.0 g, 134 mmol, 89.7% yield) was obtained as a white solid.

Step 2: ethyl N—[N-(tert-butoxycarbonyl)-L-alanyl]cyclopropanecarboximidate

[0822] ##STR00122##

[0823] Ethyl cyclopropanecarboximidate hydrochloride (15.0 g, 100.7 mmol, 1.00 eq) was dissolved in THF (105 mL). N-(tert-butoxycarbonyl)-L-alanine (15.4 g, 103 mmol, 1.30 eq) and HATU (33.2 g, 87.2 mmol, 1.10 eq) were added. Then DIPEA (30.7 g, 238 mmol, 41.4 mL, 3.00 eq) was added at 0° C. The mixture was stirred at 25° C. for 3 h. TLC (petroleum ether/ethyl acetate=5/1) indicated that the starting material was consumed completely. Crude ethyl N—[N-(tert-butoxycarbonyl)-L-alanyl]cyclopropanecarboximidate was obtained in solution and used into the next step without further work-up and purification.

Step 3: methyl 2-(5-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}-3-cyclopropyl-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxylate

[0824] ##STR00123##

[0825] To the solution of step 2 (ethyl N—[N-(tert-butoxycarbonyl)-L-alanyl]cyclopropanecarboximidate in THF, 22.0 g, 77.4 mmol, 1.00 eq), methyl 2-hydrazino-1,3-thiazole-5-carboxylate (13.4 g, 77.4 mmol, 1.00 eq) was added at 25° C. The mixture was stirred at 25° C. for 16 h. TLC (petroleum ether/ethyl acetate=3/1) indicated starting materials were consumed completely. A saturated aqueous solution of NaHCO.sub.3 was added and then the mixture was extracted with EtOAc (3×50.0 mL). The combined organic layers were washed with water and brine and concentrated in vacuum. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=100/1 to 5/1) to obtain methyl 2-(5-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}-3-cyclopropyl-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxylate (7.20 g, 18.1 mmol, 23.4% yield, 98.8% purity) as a white solid.

[0826] ESI mass [m/z]: 394.1 [M+H].sup.+

[0827] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ=8.37 (s, 1H), 7.60 (br d, J=7.0 Hz, 1H), 5.51 (br t, J=7.0 Hz, 1H), 3.87 (s, 3H), 2.12-2.02 (m, 1H), 1.44-1.26 (m, 11H), 1.06 (br s, 1H), 1.02 (dd, J=3.5, 8.3 Hz, 2H), 0.92-0.80 (m, 2H).

[0828] Chiral purity was measured with SFC method: instrument: Waters UPCC with QDa detector; column: Chiralpak AD-3, 3 μm, ID 4.6 mm×L 100 mm; mobile phase: A: CO.sub.2 B: isopropanol (0.05% diethylamine); gradient: from 5% to 40% in 2 min and hold 40% for 1 min, then from 40% to 5% of B for 1 min; flow rate: 3.4 mL/min; column temp.: 35° C.; ABPR: 1800 psi.

[0829] Retention time 1.543 min; area 100%

Step 5: methyl 2-{5-[(1S)-1-aminoethyl]-3-cyclopropyl-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carboxylate hydrochloride (INT-32)

[0830] ##STR00124##

[0831] To a solution of methyl 2-(5-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}-3-cyclopropyl-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxylate (2.0 g, 5.1 mmol) in 20 ml dioxane was added a 4 M solution of HCl in dioxane (14.2 ml, 56.7 mmol). The mixture was stirred for 4 h at 50° C., when absence of starting material was confirmed by LCMS. The volatiles were then removed under reduced pressure to obtain as residue 2.0 g methyl 2-{5-[(1S)-1-aminoethyl]-3-cyclopropyl-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carboxylate hydrochloride which was used in the subsequent steps without further purification.

[0832] ESI mass [m/z]: 294.1 [amine+H].sup.+

[0833] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ=8.75 (br, 3H), 8.45 (s, 1H), 5.3 (br, 1H), 3.9 (s, 3H), 2.1 (m, 1H), 1.6 (m, 3H), 1.1 (m, 2H), 0.9 (m, 2H).

Step 6: methyl 2-(3-cyclopropyl-5-{(1S)-1-[3-cyclopropyl-5-(trifluoromethoxy)benzamido]ethyl}-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxylate (INT-34)

[0834] ##STR00125##

[0835] A solution of methyl 2-{5-[(1S)-1-aminoethyl]-3-cyclopropyl-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carboxylate hydrochloride 1.0 g (3.0 mmol) and 1.4 ml (7.9 mmol) DIPEA in DMF was added to a solution of 0.75 g (3.0 mmol) 3-cyclopropyl-5-(trifluoromethoxy)benzoic acid and 2.0 g (5.3 mmol) HATU [O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorphosphate] in DMF. Both DMF solutions had been previously stirred separately for 1 h. The reaction mixture was stirred overnight at room temperature after which the volatiles were removed under reduced pressure in the presence of reversed phase silica gel. Purification by reversed-phase chromatography (H.sub.2O/acetonitrile) yielded 0.763 g of the title compound.

[0836] ESI mass [m/z]: 522.2 [M+H].sup.+

[0837] .sup.1H-NMR peak list (400 MHz, DMSO-d.sub.6): see table 2.

Step 7: 2-(3-cyclopropyl-5-{(1S)-1-[3-cyclopropyl-5-(trifluoromethoxy)benzamido]ethyl}-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxylic acid (INT-35)

[0838] ##STR00126##

[0839] To a solution of methyl 2-(3-cyclopropyl-5-{(1S)-1-[3-cyclopropyl-5-(trifluoromethoxy)benzamido]ethyl}-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxylate (0.70 g, 1.3 mmol) in 10 ml THF and 1 ml of water was added lithium hydroxide hydrate (0.11 g, 2.7 mmol). The mixture was stirred overnight at room temperature. Absence of starting material was proven by LCMS and the volatiles were removed under reduced pressure. The residue was dissolved in aq. HCl and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with aq. NaCl, dried and evaporated under reduced pressure to obtain 0.65 g (93%) of the title compound.

[0840] ESI mass [m/z]: 508.3 [M+H].sup.+

[0841] .sup.1H-NMR peak list (400 MHz, DMSO-d.sub.6): see table 2.

Step 8: 2-(3-cyclopropyl-5-{(1S)-1-[3-cyclopropyl-5-(trifluoromethoxy)benzamido]ethyl}-1H-1,2,4-triazol-1-yl)-N,N-dimethyl-1,3-thiazole-5-carboxamide (example I-157)

[0842] ##STR00127##

[0843] A solution of 2-(3-cyclopropyl-5-{(1S)-1-[3-cyclopropyl-5-(trifluoromethoxy)benzamido]ethyl}-1H-1,2,4-triazol-1-yl)-1,3-thiazole-5-carboxylic acid (0.1 g, 0.2 mmol) and 0.13 g (0.35 mmol) HATU [0-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorphosphate] in 3 ml DMF was stirred for 0.5 h at room temperature. A solution of dimethylamine in THF (2 M, 0.1 ml, 0.2 mmol) and Diisopropylethylamine (0.36 ml) were added. The reaction mixture was stirred over night at room temperature and then directly purified by reversed-phase chromatography (H.sub.2O/acetonitrile) to yield 87.5 mg (79%) of the title compound.

[0844] ESI mass [m/z]: 535.4 [M+H].sup.+

[0845] .sup.1H-NMR peak list (400 MHz, DMSO-d.sub.6): see table 1.

Synthesis of 3-(difluoromethoxy)-5-[(difluoromethyl)sulfanyl]benzoic acid (INT-33)

Step 1: methyl 3-(difluoromethoxy)-5-[(triisopropylsilyl)sulfanyl]benzoate

[0846] ##STR00128##

[0847] At −78° C. H.sub.2S (5 g, 146 mmol) was condensed in THF (500 mL) after which butyl lithium (53 mL of a 2.5 M solution in hexane) was added dropwise while maintaining the temperature below −70° C. The mixture was warmed to room temperature and recooled to −78° C. Chloro(triisopropyl)silane (25.5 g, 132 mmol) was added dropwise at the same temperature and the mixture was allowed to warm to room temperature. After 1 h of stirring at room temperature the mixture was poured into ice and extracted with pentane (5×200 mL). Pure triisopropylsilanethiol (22.6 g, 118 mmol, 90% yield) was obtained after evaporation of the solvent.

[0848] To a stirred solution of triisopropylsilanethiol (22.6 g, 118 mmol) in toluene (500 mL) NaH (5.19 g, 129 mmol, 60% dispersed in oil) was added portion wise under a stream of argon. The mixture was stirred until the evolution of gas ceased. Then methyl 3-bromo-5-(difluoromethoxy)benzoate (30 g, 106 mmol), XantPhos (6.13 g, 10.6 mmol) and tris(dibenzylideneacetone)dipalladium (Pd.sub.2(dba).sub.3) (4.85 g, 5.3 mmol) were added sequentially to the reaction mixture. The mixture was stirred at 100° C. overnight, cooled to room temperature, diluted with ethyl acetate (500 mL) and filtered through a thin pad of silica gel. After evaporation of the solvent crude methyl 3-(difluoromethoxy)-5-[(triisopropylsilyl)sulfanyl]benzoate (50 g, 50% purity by LC/MS, 64 mmol, 60% yield) was obtained and used in the next step without further purification.

Step 2: methyl 3-(difluoromethoxy)-5-[(difluoromethyl)sulfanyl]benzoate

[0849] ##STR00129##

[0850] Under a stream of argon were added to a stirred solution of methyl 3-(difluoromethoxy)-5-[(triisopropylsilyl)sulfanyl]benzoate (50 g, 50% purity by LC/MS, 64 mmol) in DMF (1000 mL) sodium 2-chloro-2,2-difluoroacetate (29.3 g, 192 mmol) and cesium carbonate (62.6 g, 192 mmol). The mixture was stirred at 100° C. overnight and cooled to r.t. The solvent was evaporated. The residue was dissolved in water (1000 mL) and extracted with ethyl acetate (5×250 mL). The combined organic layers were evaparorated and methyl 3-(difluoromethoxy)-5-[(difluoromethyl)sulfanyl]benzoate (4 g, 14 mmol, 22% yield, 85% purity) was obtained after purification of the residue by column chromatography.

Step 3: 3-(difluoromethoxy)-5-[(difluoromethyl)sulfanyl]benzoic acid (INT-33)

[0851] ##STR00130##

[0852] To a stirred solution of methyl 3-(difluoromethoxy)-5-[(difluoromethyl)sulfanyl]benzoate (4 g, 14 mmol, 85% purity) in a mixture of THF (40 mL)/H.sub.2O (10 mL) at 0° C., LiOH monohydrate (0.79 g, 19 mmol) was added and the mixture was stirred overnight at room temperature. The THF was then evaporated under reduced pressure, the water phase acidified to pH 3 and extracted with MTBE (5×10 mL). Pure 3-(difluoromethoxy)-5-[(difluoromethyl)sulfanyl]benzoic acid (1.5 g, 5.5 mmol, 40% yield) was obtained after purification by preparative HPLC.

[0853] ESI mass [m/z]: 269.0 [M−H].sup.−

[0854] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=13.7 (br s, 1H), 7.94 (s, 1H), 7.80-7.40 (m, 4H).

Synthesis of 3-chloro-5-(difluoromethyl)benzoic acid

Step 1: 0-(3-chloro-5-cyanophenyl) dimethylcarbamothioate

[0855] ##STR00131##

[0856] 38.9 mL (279 mmol) triethylamine, 1.14 g (9.3 mmol) N,N-dimethylpyridin-4-amine (DMAP) and 13.8 g (112 mmol) dimethylcarbamothioyl chloride were successively added to a vigorously stirred suspension of 14.3 g (93 mmol) 3-chloro-5-hydroxybenzonitrile in 450 mL anhydrous EtOAc. The reaction mixture was brought to 55-60° C. and was stirred at this temperature for 24 h. After cooling down to room temperature the reaction mixture was washed with 450 mL water and 450 mL brine. The organic layer was separated, dried over Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuo to a volume of about 50 mL. The concentrate was diluted with 150 mL n-hexane, the precipitate formed was filtered off, washed with 150 mL of a 1:1 mixture diethyl ether and n-hexane and vacuum dried at 60° C. (1 tor, 3 h) to give 9.3 g (86%) of O-(3-chloro-5-cyanophenyl) dimethylcarbamothioate as colorless crystals.

[0857] .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 3.35 (s, 3H), 3.46 (s, 3H), 7.30 (s, 1H), 7.35 (s, 1H), 7.53 (s, 1H) (measured on a Varian Gemini 2000 machine).

Step 2: S-(3-chloro-5-cyanophenyl) dimethylcarbamothioate

[0858] ##STR00132##

[0859] A solution of 2.41 g (10 mmol)O-(3-chloro-5-cyanophenyl) dimethylcarbamothioate in 20 mL anhydrous dimethyl acetamide was heated in a Biotage Initiator microwave for 35 min at 220° C. The reaction mixture was brought to room temperature and diluted with water 40 ml. The precipitate formed was filtered off, washed with hot (ca. 70° C.) water and n-hexane and vacuum dried at 60° C. (1 tor, 3 h) to give 2.05 g (85%) of S-(3-chloro-5-cyanophenyl) dimethylcarbamothioate as a white powder.

[0860] .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 3.05 (s, 3H), 3.10 (s, 3H), 7.64 (s, 1H), 7.69 (s, 1H), 7.73 (s, 1H) (measured on a Varian Gemini 2000 machine).

Step 3: 3-chloro-5-sulfanylbenzoic acid

[0861] ##STR00133##

[0862] A hot (ca. 70° C.) solution of 68.5 g (1.71 mol) NaOH in 300 mL water was added to a suspension of 27.5 g (114 mmol)S-(3-chloro-5-cyanophenyl) dimethylcarbamothioate in 700 mL warm (ca. 40° C.) methanol. The reaction mixture was stirred under reflux (20 h). Methanol was removed in vacuo and the aqueous solution was washed with 2×200 mL diethyl ether. The aqueous layer was separated and added dropwise to a suspension of 300 g ice in concentrated aqueous HCl (under argon, cooling with ice bath). The solution formed was filtered off, washed with 2×50 mL water, 50 mL n-hexane and vacuum dried at 60° C. (1 tor, 3 h) to give 21.2 g (98%) of 3-chloro-5-sulfanylbenzoic acid as a white powder.

[0863] .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 3.65 (s, 1H), 7.50 (s, 1H), 7.86 (s, 1H), 7.89 (s, 1H), 10.80 (brs, 1H) (measured on a Varian Gemini 2000 machine).

Step 4: 3-chloro-5-[(difluoromethyl)sulfanyl]benzoic acid

[0864] ##STR00134##

[0865] 12.44 g (90 mmol) K.sub.2CO.sub.3 and 18.3 g (120 mmol) sodium chloro(difluoro)acetate were added successively to a solution of 11.32 g (60 mmol) 3-chloro-5-sulfanylbenzoic acid in anhydrous DMF under argon atmosphere. The reaction mixture was stirred at 95-100° C. for 3 h. Caution: At 90-95° C. CO.sub.2 evolved vigorously! The volatiles were removed in vacuo and the residue was diluted with water to a volume of 500 ml. The product was extracted with diethyl ether. The aqueous layer was separated and added dropwise to the suspension of ca. 100 g ice in 200 mL 5% hydrochloric acid. The suspension was stirred at room temperature for 20 h, the precipitate was filtered off, washed with water 2×50 mL and a 1/1 mixture of n-hexane and diethylether. Vacuum drying 60° C. (1 tor, 3 h) gave 11 g of crude product (85% pure according to 1H and 19F NMR). Sublimation at 90-95° C./0.01 tor afforded 7.7 g (54%) of 3-chloro-5-[(difluoromethyl)sulfanyl]benzoic acid as white powder.

[0866] .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 6.90 (t, 1H, J=74.4 Hz), 7.83 (t, 1H, J=2 Hz), 8.14 (t, 1H, J=2 Hz), 8.20 (s, 1H), 10.50 (br s, 1H). (measured on a Varian Gemini 2000 machine).

Synthesis of 3-chloro-5-[(difluoromethyl)sulfonyl]benzoic acid

[0867] ##STR00135##

[0868] Oxone (41.2 g, 67 mmol) was added in one portion to a stirred solution of 3-chloro-5-[(difluoromethyl)sulfanyl]benzoic acid (8.0 g, 33.5 mmol) in methanol (200 ml) and water (50 ml). The reaction mixture was stirred at 25° C. for 48 h. It was filtered and the filter-cake was washed with methanol.

[0869] The combined filtrates were concentrated in vacuo and diluted with water. A white precipitate formed which was filtered, washed with water and dried in oven at 100° C. to give 8.95 g of a white powder which was purified on CombiFlash to give 6.9 g (76%) of the pure acid.

[0870] .sup.1H-NMR (400 MHz, CD.sub.3OD) δ=8.46 (s, 1H), 8.39 (s, 1H), 8.07 (s, 1H), 6.85 (t, 1H, J=52.7 Hz). (measured on a Varian Gemini 2000 machine).

Synthesis of 3-(difluoromethylsulfonyl)-5-(trifluromethoxy)benzoic acid

Step 1: methyl 3-(trifluoromethoxy)-5-triisopropylsilylsulfanyl-benzoate

[0871] ##STR00136##

[0872] To a stirred solution of triisopropylsilanethiol (21.45 g, 112 mmol) in toluene (500 mL), under a stream of argon, NaH (5.03 g, 122 mmol, 60% disperse in oil) was added in portions. The mixture was stirred until no more gas evolved. Then methyl 3-bromo-5-(trifluoromethoxy)benzoate (CAS: 1306763-53-0) (30 g, 100 mmol), XantPhos (6.13 g, 11.2 mmol) and Pd.sub.2(dba).sub.3 (4.85 g, 5.3 mmol) were added to the reaction mixture sequentially. The mixture was stirred at 100° C. overnight, cooled to r.t., diluted with EtOAc (500 mL) and filtered through a thin pad of silica gel. After evaporation, crude methyl 3-(trifluoromethoxy)-5-triisopropylsilylsulfanyl-benzoate (50 g, 50% purity by LC/MS, 64 mmol, 57% yield) was obtained and used in the next step without further purification.

Step 2: methyl 3-(difluoromethylsulfanyl)-5-(trifluoromethoxy)benzoate

[0873] ##STR00137##

[0874] To a stirred solution of crude methyl 3-(trifluoromethoxy)-5-triisopropylsilylsulfanyl-benzoate (50 g, 50% purity by LC/MS, 64 mmol) in DMF (1000 mL) sodium 2-chloro-2,2-difluoroacetate (29.27 g, 192 mmol) and cesium carbonate (62.55 g, 192 mmol) were added under a stream of argon. The mixture was stirred at 100° C. overnight, cooled to r.t., and evaporated under reduced pressure. The residue was dissolved in water (1000 mL) and extracted with EtOAc (5×250 mL). Methyl 3-(difluoromethylsulfanyl)-5-(trifluoromethoxy)benzoate (10.5 g, 34.7 mmol, 54.3% yield) was obtained after column chromatography.

Step 3: methyl 3-(difluoromethylsulfonyl)-5-(trifluoromethoxy)benzoate

[0875] ##STR00138##

[0876] To a solution of methyl 3-(difluoromethylsulfanyl)-5-(trifluoromethoxy)benzoate (10.5 g, 34.7 mmol) in dichloromethane (200 mL) mCPBA (16.35 g, 93.9 mmol, 75% purity) was added in portions at 0° C. under a stream of argon. The mixture was stirred overnight at room temperature and evaporated under reduced pressure. Methyl 3-(difluoromethylsulfonyl)-5-(trifluoromethoxy)benzoate (6.8 g, 20.34 mmol, 58.63%) was obtained after column chromatography on silica gel.

Step 4: 3-(difluoromethylsulfonyl)-5-(trifluromethoxy)benzoic acid

[0877] ##STR00139##

[0878] To a stirred solution of methyl 3-(difluoromethylsulfonyl)-5-(trifluoromethoxy)benzoate (6.8 g, 20.34 mmol) in THF (80 mL)/water (20 mL) mixture at 0° C. LiOH monohydrate (1.146 g, 27.459 mmol) was added and the mixture was stirred overnight at r.t. THF was evaporated under reduced pressure, the water phase was acidified to pH=3 and extracted with MTBE (5×10 mL). Pure 3-(difluoromethylsulfonyl)-5-(trifluromethoxy)benzoic acid (3 g, 9.37 mmol, 34.12% yield) was obtained after recrystallization from 30% aqueous EtOH as white solid.

[0879] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ=7.47 (t, 1H), 8.21 (s, 1H), 8.32 (s, 1H), 8.40 (s, 1H), 13.79 (s, 1H).

[0880] ESI mass [m/z]: 319.0 [M+H].sup.+

Synthesis of N-{1-[1-(5-cyano-1,3-thiazol-2-yl)-3-methoxy-1H-1,2,4-triazol-5-yl]ethyl}-3-(cyclopropylsulfonyl)-5-(trifluoromethoxy)benzamide (example I-200)

Step 1: O-methyl [2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl]carbamothioate

[0881] ##STR00140##

[0882] To a solution of 2.00 g (9.12 mmol) 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoic acid in dichloromethane (15 ml) was added at 0° C. 1.59 ml (18.2 mmol) oxalyl chloride and 0.04 mL N,N-dimethylformamide. The reaction mixture was stirred for 30 min at 0° C. and 4 h at room temperature. After this time the solvent and excess oxalyl chloride were evaporated under reduced pressure.

[0883] The crude residue was dissolved in acetone (15 ml) and then 1.33 g (13.6 mmol) KSCN were added dropwise as a solution in acetone (20 ml). The addition funnel was rinsed with 5 ml acetone and the mixture was stirred at 60° C. for 2 h. After cooling to 50° C. 0.92 ml (23 mmol) of methanol were added and the mixture was stirred at 55° C. overnight, cooled to room temperature and evaporated under reduced pressure. The resulting residue was suspended in a mixture of water and EtOAc. After separation of the layers the aqueous phase was extracted with EtOAc. The combined organic layers were washed with water and brine respectively and finally the organic layer was dried over anhydrous Na.sub.2SO.sub.4 and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography to yield 1.66 g of the title compound.

[0884] ESI mass [m/z]: 293.1 [M+H].sup.+

Step 2: 2-{5-[1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-methoxy-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carbonitrile

[0885] ##STR00141##

[0886] To a solution of 700 mg (2.39 mmol) O-methyl [2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl]carbamothioate in ethanol (15 ml) were added 0.34 g (2.4 mmol) 2-hydrazino-1,3-thiazole-5-carbonitrile and the reaction mixture was stirred overnight at 75° C. It was then stirred for 8 h at 80° C. and again overnight at 75° C. This cycle was repeated once more after which near complete conversion of the starting material was observed. The mixture was cooled to room temperature, diluted with acetonitrile and purified by HPLC (H.sub.2O/acetonitrile). This provided two fractions of the title compound in low purity. The two fractions were combined and repurified by HPLC (H.sub.2O/acetonitrile) providing 150 mg 2-{5-[1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-methoxy-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carbonitrile.

[0887] ESI mass [m/z]: 381.0 [M+H].sup.+

[0888] .sup.1H-NMR (400 MHz, DMSO-d6): δ=8.35 (s, 1H), 7.85 (s, 4H), 5.92 (q, J=6.8 Hz, 1H), 3.99 (s, 3H), 1.79 (d, J=7.2 Hz, 3H).

Step 3: 2-[5-(1-aminoethyl)-3-methoxy-1H-1,2,4-triazol-1-yl]-1,3-thiazole-5-carbonitrile (INT-37)

[0889] ##STR00142##

[0890] A solution of 129 mg (0.33 mmol) 2-{5-[1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-methoxy-1H-1,2,4-triazol-1-yl}-1,3-thiazole-5-carbonitrile and 0.05 mL (1 mmol) hydrazine hydrate in 2 mL methanol was stirred for 70 min at room temperature. At this point all of the starting material had converted to a mixture of N-{1-[1-(5-cyano-1,3-thiazol-2-yl)-3-methoxy-1H-1,2,4-triazol-5-yl]ethyl}-2-(hydrazinocarbonyl)benzamide and the desired product as determined by HPLC/MS. 3 ml of 1 M hydrochloric acid were added and the resulting mixture was further stirred overnight at room temperature. HPLC/MS showed full conversion of the intermediate N-{1-[1-(5-cyano-1,3-thiazol-2-yl)-3-methoxy-1H-1,2,4-triazol-5-yl]ethyl}-2-(hydrazinocarbonyl)benzamide to the desired product. The pH of the reaction mixture was then adjusted to pH 8 by the addition of a sat. aqueous solution of NaHCO.sub.3. Water was added, and the mixture repeatedly extracted with ethyl acetate. The combined organic layers were washed with brine, dried using Na.sub.2SO.sub.4, filtered and the solvent was evaporated under reduced pressure to yield 80 mg of a residue containing 2-[5-(1-aminoethyl)-3-methoxy-1H-1,2,4-triazol-1-yl]-1,3-thiazole-5-carbonitrile which was used for the next step without further purification.

[0891] ESI mass [m/z]: 251.1 [M+H].sup.+

[0892] .sup.1H-NMR (400 MHz, DMSO-d6): δ=8.59 (s, 1H), 4.70 (q, 1H, J=6.8 Hz), 3.97 (s, 3H), 1.39 (d, 3H, J=6.8 Hz).

Step 4: N-{1-[1-(5-cyano-1,3-thiazol-2-yl)-3-methoxy-1H-1,2,4-triazol-5-yl]ethyl}-3-(cyclopropyl-sulfonyl)-5-(trifluoromethoxy)benzamide (example I-200)

[0893] ##STR00143##

[0894] A solution of 106 mg (343 μmol) 3-(cyclopropylsulfonyl)-5-(trifluoromethoxy)benzoic acid, 236 mg (623 μmol) HATU, 0.19 mL (1.1 mmol)N-ethyldiisopropylamine in 2 mL DMF was stirred for 60 min at room temperature. 78 mg of the crude product obtained in step 3 were then added and the mixture stirred over night. The reaction mixture was then diluted with 1 mL acetonitrile and purified directly by HPLC (H.sub.2O/acetonitrile) to provide 76 mg N-{1-[1-(5-cyano-1,3-thiazol-2-yl)-3-methoxy-1H-1,2,4-triazol-5-yl]ethyl}-3-(cyclopropylsulfonyl)-5-(trifluoromethoxy)benzamide.

[0895] ESI mass [m/z]: 543.1 [M+H].sup.+

[0896] .sup.1H-NMR peak list (400 MHz, DMSO-d.sub.6): see table 1.

Analytical Data of the Compounds

[0897] The determination of [M+H].sup.+ or [M−H].sup.− by LC-MS under acidic chromatographic conditions was done with 1 ml formic acid per liter acetonitrile and 0.9 ml formic acid per liter Millipore water as eluents. The column Zorbax Eclipse Plus C18 50 mm*2.1 mm was used. The temperature of the column oven was 55° C.

Instruments:

[0898] LC-MS3: Waters UPLC with SQD2 mass spectrometer and SampleManager autosampler. Linear gradient 0.0 to 1.70 minutes from 10% acetonitrile to 95% acetonitrile, from 1.70 to 2.40 minutes constant 95% acetonitrile, flow 0.85 ml/min.

[0899] LC-MS6 and LC-MS7: Agilent 1290 LC, Agilent MSD, HTS PAL autosampler. Linear gradient 0.0 to 1.80 minutes from 10% acetonitrile to 95% acetonitrile, from 1.80 to 2.50 minutes constant 95% acetonitrile, flow 1.0 ml/min.

[0900] The determination of [M+H].sup.+ by LC-MS under neutral chromatographic conditions was done with acetonitrile and Millipore water containing 79 mg/i ammonia carbonate as eluents.

[0901] Instruments:

[0902] LC-MS4: Waters IClass Acquity with QDA mass spectrometer and FTN autosampler (column Waters Acquity 1.7 μm 50 mm*2.1 mm, oven temperature 45° C.). Linear gradient 0.0 to 2.10 minutes from 10% acetonitrile to 95% acetonitrile, from 2.10 to 3.00 minutes constant 95% acetonitrile, flow 0.7 ml/min.

[0903] LC-MS5: Agilent 1100 LC system with MSD mass spectrometer and HTS PAL autosampler (column: Zorbax XDB C18 1.8 μm 50 mm*4.6 mm, oven temperature 55° C.). Linear gradient 0.0 to 4.25 minutes from 10% acetonitrile to 95% acetonitrile, from 4.25 to 5.80 minutes constant 95% acetonitrile, flow 2.0 ml/min.

[0904] The enantomeric excess of certain intermediates, e.g. tert-butyl {(1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}carbamate, was determined using chiral HPLC: Chiralcel OD-RH column (4.6 mm×150 mm×5 μm), room temperature, eluting with 0.1% phosphoric acid (A) and acetonitrile (B), gradient A:B 95/5 to 10/90, detecting at 210 nm.

[0905] Optical rotations were measured using a Perkin Elmer model 341 polarimeter at a wavelength of 589 nm, a pathlength of 10 cm and a temperature of 20° C. They are reported as specific rotations including the concentration “c” of the measured compound (in g/100 mL) and the solvent used.

[0906] The determination of the .sup.1H NMR data was effected with a Bruker Avance III 400 Mhz equipped with a 1.7 mm TCI cryo probe, a Bruker Avance III 600 Mhz equipped with a 5 mm multi-nuclear cryo probe or a Bruker Avance NEO 600 Mhz equipped with a 5 mm TCI cryo probe with tetramethylsilane as reference (0.0) and the solvents CD.sub.3CN, CDCl.sub.3 or D.sub.6-DMSO.

[0907] The NMR data of selected examples are listed either in conventional form (8 values in ppm, multiplet splitting, number of hydrogen atoms) or as NMR peak lists.

NMR peak list method

[0908] The .sup.1H NMR data of selected examples are stated in the form of .sup.1H NMR peak lists. For each signal peak, first the 6 value in ppm and then the signal intensity in round brackets are listed. The pairs of 6 value-signal intensity numbers for different signal peaks are listed with separation from one another by semicolons.

[0909] The peak list for one example therefore takes the form of:

δ.sub.1 (intensity.sub.1); δ.sub.2 (intensity.sub.2); . . . ; δ.sub.i (intensity.sub.i); . . . ; δ.sub.n (intensity.sub.n)

[0910] The intensity of sharp signals correlates with the height of the signals in a printed example of an NMR spectrum in cm and shows the true ratios of the signal intensities. In the case of broad signals, several peaks or the middle of the signal and the relative intensity thereof may be shown in comparison to the most intense signal in the spectrum.

[0911] For calibration of the chemical shift of .sup.1H NMR spectra, we use tetramethylsilane and/or the chemical shift of the solvent, particularly in the case of spectra which are measured in DMSO. Therefore, the tetramethylsilane peak may but need not occur in NMR peak lists.

[0912] The lists of the .sup.1H NMR peaks are similar to the conventional .sup.1H NMR printouts and thus usually contain all peaks listed in a conventional NMR interpretation.

[0913] In addition, like conventional .sup.1H NMR printouts, they may show solvent signals, signals of stereoisomers of the target compounds which are likewise provided by the invention, and/or peaks of impurities.

[0914] In the reporting of compound signals within the delta range of solvents and/or water, our lists of .sup.1H NMR peaks show the standard solvent peaks, for example peaks of DMSO in DMSO-D.sub.6 and the peak of water, which usually have a high intensity on average.

[0915] The peaks of stereoisomers of the target compounds and/or peaks of impurities usually have a lower intensity on average than the peaks of the target compounds (for example with a purity of >90%).

[0916] Such stereoisomers and/or impurities may be typical of the particular preparation process. Their peaks can thus help in identifying reproduction of our preparation process with reference to “by-product fingerprints”.

[0917] A person skilled in the art calculating the peaks of the target compounds by known methods (MestreC, ACD simulation, but also with empirically evaluated expected values) can, if required, isolate the peaks of the target compounds, optionally using additional intensity filters. This isolation would be similar to the peak picking in question in conventional .sup.1H NMR interpretation.

[0918] Further details of .sup.1H NMR peak lists can be found in the Research Disclosure Database Number 564025.

[0919] The compounds according to the invention described in table 1 below are likewise preferred compounds of the formula (I), wherein R.sup.1 is hydrogen, R.sup.3 is hydrogen, and X is oxygen and which are obtained according to or analogously to the preparation examples described above.

##STR00144##

TABLE-US-00001 TABLE 1 ESI Mass Example Structure.sup.1) NMR Peak List.sup.2) (m/z).sup.3) I-1 [00145] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5318 (2.7); 9.5154 (2.7); 8.6692 (16.0); 8.3228 (12.3); 8.3156 (0.5); 8.2159 (5.0); 8.1675 (4.8); 8.0955 (4.5); 6.0739 (0.4); 6.0569 (1.9); 6.0399 (3.0); 6.0228 (1.9); 6.0056 (0.4); 4.0561 (1.0); 4.0382 (3.2); 4.0204 (3.2); 4.0026 (1.1); 3.3205 (31.9); 2.6804 (0.4); 2.6759 (0.9); 2.6713 (1.2); 2.6668 (0.8); 2.6621 (0.4); 2.5248 (3.4); 2.5200 (5.3); 2.5113 (69.7); 2.5069 (141.9); 2.5023 (186.4); 2.4977 (132.6); 2.4932 (62.6); 2.3380 (0.4); 2.3337 (0.8); 2.3292 (1.1); 2.3246 (0.8); 2.3201 (0.4); 1.9890 (14.2); 1.6369 (12.0); 1.6194 (12.0); 1.3978 (6.6); 1.1932 (3.9); 1.1754 (7.8); 1.1576 (3.8); 0.1459 (0.6); 0.0080 (4.9); −0.0002 (144.6); −0.0085 (4.7); −0.1496 (0.6) 427.1 I-2 [00146] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6855 (2.5); 9.6691 (2.7); 9.6466 (0.7); 8.6732 (16.0); 8.5114 (10.3); 8.3436 (4.1); 8.3321 (12.1); 8.3161 (0.4); 8.2130 (3.2); 7.8004 (1.7); 7.7916 (2.8); 7.7635 (2.8); 7.7548 (1.8); 6.1147 (0.4); 6.1066 (0.6); 6.0973 (1.8); 6.0894 (1.1); 6.0803 (2.6); 6.0724 (0.8); 6.0632 (1.7); 6.0462 (0.4); 3.3240 (80.4); 2.6769 (0.7); 2.6723 (0.9); 2.6677 (0.7); 2.5258 (2.6); 2.5210 (4.0); 2.5123 (56.4); 2.5079 (117.7); 2.5033 (156.2); 2.4987 (111.3); 2.4942 (52.9); 2.3347 (0.7); 2.3301 (0.9); 2.3254 (0.7); 2.3212 (0.3); 1.9896 (1.2); 1.6594 (12.9); 1.6419 (13.0); 1.3977 (3.1); 1.1759 (0.6); 0.1459 (0.4); 0.0080 (2.7); −0.0002 (86.7); −0.0085 (3.0); −0.1497 (0.3) 461.1 I-3 [00147] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6710 (1.5); 9.6540 (1.6); 8.5442 (5.6); 8.3448 (2.5); 8.1330 (0.4); 6.1164 (1.0); 6.0992 (1.5); 6.0818 (1.0); 3.6687 (0.8); 3.5605 (1.8); 3.5477 (2.5); 3.5351 (1.1); 3.3336 (21.6); 3.2773 (21.0); 3.2389 (0.4); 3.0116 (0.4); 2.5271 (1.3); 2.5136 (19.8); 2.5095 (37.6); 2.5050 (47.9); 2.5005 (34.8); 2.4962 (17.0); 2.3331 (16.0); 1.6462 (6.0); 1.6288 (5.9); 0.0078 (1.2); −0.0002 (27.1); −0.0085 (0.9) 565.4 I-4 [00148] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6674 (1.5); 9.6504 (1.5); 8.5421 (5.4); 8.3434 (2.4); 6.1187 (1.0); 6.1015 (1.5); 6.0843 (1.0); 3.3735 (1.2); 3.3338 (39.8); 3.3004 (0.6); 3.2380 (0.4); 2.5271 (1.1); 2.5137 (19.3); 2.5094 (37.5); 2.5049 (48.8); 2.5004 (35.8); 2.4960 (17.8); 2.3351 (16.0); 1.6486 (5.7); 1.6312 (5.7); 1.0758 (0.5); 1.0699 (0.5); 1.0659 (0.4); 1.0580 (0.7); 1.0454 (0.5); 1.0391 (0.5); 0.5238 (0.6); 0.5128 (1.9); 0.5095 (2.0); 0.4929 (1.9); 0.4895 (1.9); 0.4792 (0.6); 0.2664 (1.0); 0.0079 (1.2); −0.0002 (27.0); −0.0085 (1.0) 561.4 I-5 [00149] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6696 (1.6); 9.6525 (1.5); 8.5432 (5.4); 8.3462 (2.5); 8.1404 (1.3); 8.1339 (6.9); 6.1335 (0.3); 6.1167 (1.2); 6.0995 (1.7); 6.0821 (1.0); 3.3333 (82.0); 3.2462 (1.8); 3.2377 (1.7); 3.0278 (1.8); 2.6768 (0.6); 2.6725 (0.7); 2.6681 (0.5); 2.5123 (66.0); 2.5081 (95.2); 2.5036 (106.4); 2.4990 (72.5); 2.4946 (33.6); 2.3316 (16.0); 1.6453 (6.2); 1.6279 (5.6); 0.0075 (9.0); −0.0002 (50.3); −0.0085 (2.0) 521.4 I-6 [00150] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6672 (1.4); 9.6501 (1.4); 8.5406 (5.1); 8.3452 (2.3); 6.1151 (1.0); 6.0980 (1.6); 6.0807 (1.0); 3.5029 (0.7); 3.3324 (51.4); 3.2346 (0.6); 3.2228 (0.6); 2.6774 (0.4); 2.6730 (0.5); 2.6686 (0.4); 2.5263 (1.6); 2.5128 (28.6); 2.5085 (56.0); 2.5040 (72.3); 2.4994 (52.6); 2.4950 (25.8); 2.3330 (16.0); 1.6460 (5.6); 1.6285 (5.6); 1.1507 (1.1); 0.0079 (1.4); −0.0002 (38.2); −0.0085 (1.4) 535.4 I-7 [00151] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6650 (1.5); 9.6481 (1.6); 8.5440 (5.6); 8.3460 (2.5); 8.2917 (3.1); 6.1271 (1.1); 6.1098 (1.7); 6.0926 (1.1); 3.3352 (37.6); 3.1605 (0.7); 3.0153 (10.0); 2.6738 (0.3); 2.5269 (1.2); 2.5134 (22.4); 2.5093 (43.2); 2.5048 (55.3); 2.5003 (40.6); 2.4963 (20.4); 2.3347 (16.0); 1.6509 (5.8); 1.6335 (5.8); 0.9090 (0.4); 0.8946 (0.7); 0.8836 (0.8); 0.8764 (1.0); 0.8706 (1.3); 0.8589 (0.8); 0.8533 (1.0); 0.8357 (0.5); 0.7686 (0.5); 0.7551 (0.5); 0.7442 (0.9); 0.7393 (0.9); 0.7343 (1.2); 0.7265 (1.2); 0.7167 (1.2); 0.7059 (0.8); 0.6959 (0.5); 0.6814 (0.3); 0.0078 (1.0); −0.0002 (26.6); −0.0084 (1.2) 547.4 I-8 [00152] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6649 (1.3); 9.6479 (1.3); 8.5427 (6.0); 8.3406 (2.7); 8.1776 (0.5); 6.1203 (0.9); 6.1032 (1.4); 6.0859 (0.9); 3.3383 (16.8); 3.2539 (1.4); 3.2368 (0.9); 2.5304 (0.6); 2.5127 (19.2); 2.5083 (24.5); 2.5039 (18.2); 2.3371 (16.0); 2.0018 (0.5); 1.6512 (6.2); 1.6338 (6.1); 0.8727 (3.2); 0.0073 (0.5); −0.0002 (11.0); −0.0084 (0.5) 563.4 I-9 [00153] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6816 (1.6); 9.6646 (1.6); 8.5484 (5.9); 8.3446 (2.6); 8.2613 (1.7); 6.1289 (1.1); 6.1117 (1.7); 6.0945 (1.1); 4.6191 (1.9); 3.3362 (22.4); 2.5110 (25.3); 2.5066 (32.0); 2.5021 (23.5); 2.3425 (16.0); 2.0791 (1.5); 1.6534 (6.0); 1.6359 (6.0); 0.0079 (0.7); −0.0002 (17.4); −0.0085 (0.7) 546.4 I-10 [00154] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6708 (1.4); 9.6537 (1.4); 8.5450 (5.1); 8.3446 (2.4); 6.1188 (1.1); 6.1016 (1.7); 6.0843 (1.1); 3.3389 (13.8); 3.0388 (0.5); 2.5311 (0.5); 2.5176 (8.2); 2.5132 (16.3); 2.5087 (21.4); 2.5041 (15.7); 2.4997 (7.8); 2.3372 (16.0); 2.0812 (0.5); 1.6511 (5.8); 1.6336 (5.7); 1.1804 (4.4); 1.1650 (4.3); 0.0080 (0.4); −0.0002 (12.1); −0.0085 (0.5) 549.4 I-11 [00155] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6743 (1.5); 9.6573 (1.6); 8.5427 (5.6); 8.3413 (2.5); 8.2850 (0.6); 6.1255 (1.0); 6.1083 (1.6); 6.0910 (1.0); 4.4278 (0.8); 4.4062 (0.9); 3.3908 (1.2); 3.3357 (17.8); 2.5288 (0.7); 2.5153 (12.6); 2.5110 (24.8); 2.5066 (32.1); 2.5020 (23.7); 2.4977 (11.8); 2.3410 (16.0); 1.6527 (5.9); 1.6353 (5.8); 0.0079 (0.6); −0.0002 (16.7); −0.0085 (0.6) 589.4 I-12 [00156] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3668 (1.4); 9.3500 (1.4); 8.6325 (7.6); 8.0393 (1.9); 8.0353 (3.3); 8.0314 (2.2); 7.9504 (1.6); 7.9458 (3.5); 7.9413 (2.2); 7.9311 (2.6); 7.9274 (3.1); 7.9229 (1.6); 5.9983 (1.0); 5.9812 (1.6); 5.9642 (1.0); 3.3294 (121.2); 2.6763 (0.5); 2.6717 (0.7); 2.6672 (0.5); 2.5251 (2.2); 2.5203 (3.4); 2.5116 (43.0); 2.5072 (86.9); 2.5027 (113.8); 2.4981 (82.2); 2.4936 (39.8); 2.3432 (16.0); 2.3344 (1.0); 2.3295 (0.9); 2.3249 (0.6); 2.0751 (2.0); 1.5936 (5.6); 1.5762 (5.6); 0.1459 (0.4); 0.0080 (3.3); −0.0002 (99.3); −0.0085 (3.7); −0.1495 (0.4) 453.0 I-13 [00157] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3711 (1.4); 9.3544 (1.4); 8.6349 (6.1); 8.0638 (16.0); 5.9977 (1.0); 5.9805 (1.5); 5.9635 (1.0); 3.3684 (205.5); 3.3621 (206.6); 3.3548 (247.8); 2.6799 (1.0); 2.6754 (1.3); 2.6710 (1.0); 2.5287 (4.1); 2.5151 (85.8); 2.5109 (167.8); 2.5065 (216.4); 2.5019 (157.0); 2.4977 (76.8); 2.3459 (15.5); 2.3333 (1.6); 2.3288 (1.2); 2.0779 (0.4); 1.5942 (5.6); 1.5768 (5.7); 0.0029 (0.4) 496.9 I-14 [00158] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5184 (1.4); 9.5016 (1.4); 8.6375 (5.6); 8.3725 (2.5); 8.2162 (2.7); 8.2120 (2.8); 8.2072 (2.5); 6.0376 (1.0); 6.0207 (1.5); 6.0035 (1.0); 3.3658 (92.0); 3.3593 (86.3); 3.3576 (85.4); 3.3534 (92.8); 2.6799 (0.4); 2.6755 (0.6); 2.6709 (0.4); 2.5289 (1.9); 2.5154 (37.2); 2.5110 (75.0); 2.5065 (98.2); 2.5019 (70.6); 2.4974 (33.9); 2.3481 (16.0); 2.3382 (0.8); 2.3334 (0.8); 2.3288 (0.5); 1.6164 (5.7); 1.5990 (5.7) 486.1 I-15 [00159] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4311 (1.5); 9.4144 (1.5); 8.6322 (7.6); 8.3721 (1.5); 8.3677 (3.3); 8.3642 (3.0); 8.3592 (2.8); 8.3553 (3.5); 8.3508 (1.5); 8.3066 (2.5); 8.3031 (3.7); 8.2996 (1.9); 6.0178 (1.0); 6.0007 (1.6); 5.9836 (1.0); 3.3295 (71.0); 2.6763 (0.4); 2.6721 (0.5); 2.6676 (0.3); 2.5252 (1.7); 2.5117 (31.1); 2.5076 (59.8); 2.5031 (76.4); 2.4985 (55.1); 2.4942 (26.9); 2.3455 (16.0); 2.3301 (0.7); 2.3255 (0.5); 2.0754 (1.7); 1.6039 (5.8); 1.5865 (5.7); 0.0079 (2.4); −0.0002 (57.2); −0.0085 (2.3) 444.1 I-16 [00160] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5806 (1.3); 9.5641 (1.4); 8.6405 (7.1); 8.6090 (2.7); 8.5791 (2.4); 8.4964 (2.3); 6.0612 (1.0); 6.0441 (1.6); 6.0271 (1.0); 3.3340 (109.3); 2.6796 (0.5); 2.6751 (0.7); 2.6706 (0.5); 2.5286 (2.1); 2.5151 (43.4); 2.5107 (88.2); 2.5062 (116.0); 2.5016 (84.4); 2.4971 (41.3); 2.3514 (16.0); 2.3377 (0.7); 2.3330 (0.8); 2.3285 (0.6); 2.0796 (0.4); 1.6291 (5.5); 1.6117 (5.5) 432.1 I-17 [00161] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4342 (1.4); 9.4176 (1.5); 8.6353 (7.4); 8.1718 (2.0); 8.1682 (3.2); 8.1645 (2.0); 7.9155 (2.1); 7.8348 (2.0); 7.8325 (2.1); 6.0169 (1.0); 5.9998 (1.6); 5.9827 (1.0); 3.3358 (33.3); 2.5283 (0.6); 2.5149 (11.4); 2.5106 (22.3); 2.5061 (28.8); 2.5016 (20.8); 2.4971 (10.1); 2.3478 (16.0); 2.0793 (0.3); 1.6082 (5.7); 1.5907 (5.6) 501.0 I-18 [00162] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4457 (1.4); 9.4290 (1.4); 8.6359 (7.3); 8.1139 (2.3); 8.0518 (2.5); 7.8518 (2.2); 7.2481 (1.1); 7.1097 (2.5); 6.9714 (1.2); 6.0267 (1.1); 6.0096 (1.6); 5.9924 (1.1); 3.3354 (28.0); 2.5278 (0.5); 2.5143 (9.5); 2.5099 (18.8); 2.5054 (24.3); 2.5009 (17.5); 2.4965 (8.5); 2.3456 (16.0); 2.0776 (3.5); 1.6111 (5.8); 1.5936 (5.7); 0.0079 (0.6); −0.0002 (16.6); −0.0085 (0.6) 423.1 I-19 [00163] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5513 (1.4); 9.5347 (1.4); 8.6356 (7.2); 8.3066 (2.6); 8.1271 (2.5); 8.0424 (2.4); 6.0440 (1.0); 6.0270 (1.6); 6.0099 (1.0); 3.3358 (24.5); 2.5288 (0.6); 2.5154 (10.9); 2.5110 (21.9); 2.5065 (28.5); 2.5019 (20.5); 2.4974 (9.9); 2.3497 (16.0); 1.6239 (5.7); 1.6064 (5.6) 491.1 I-20 [00164] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.7395 (1.4); 9.7228 (1.4); 8.6345 (7.7); 8.2844 (3.4); 8.2819 (3.6); 8.2281 (3.4); 6.0537 (1.0); 6.0366 (1.6); 6.0195 (1.0); 3.3346 (14.0); 2.5285 (0.5); 2.5150 (9.3); 2.5106 (18.6); 2.5061 (24.2); 2.5015 (17.5); 2.4970 (8.4); 2.3568 (16.0); 2.0792 (15.7); 1.6278 (5.7); 1.6104 (5.6) 442.1 I-21 [00165] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6487 (1.6); 9.6316 (1.6); 8.5273 (6.1); 8.3405 (2.7); 8.3173 (0.8); 8.2568 (6.8); 8.2318 (1.2); 7.7645 (1.2); 6.0964 (1.1); 6.0790 (1.7); 6.0617 (1.1); 3.3308 (55.9); 3.3070 (0.4); 2.6730 (0.4); 2.5083 (56.6); 2.5040 (72.8); 2.4996 (54.7); 2.3322 (16.0); 2.0763 (0.7); 1.6368 (6.0); 1.6194 (6.0); 0.0077 (2.6); −0.0002 (54.0) 493.1 I-22 [00166] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5085 (1.3); 9.4917 (1.4); 8.2380 (2.4); 8.1957 (2.4); 8.1285 (6.7); 8.0936 (2.3); 6.0751 (1.0); 6.0579 (1.5); 6.0406 (1.0); 5.7563 (0.8); 3.3257 (37.9); 3.2513 (1.2); 3.0242 (1.1); 2.6760 (0.6); 2.6716 (0.8); 2.6670 (0.6); 2.5249 (2.9); 2.5114 (51.6); 2.5071 (100.1); 2.5026 (127.9); 2.4980 (91.4); 2.4936 (43.8); 2.3287 (16.0); 1.6241 (5.4); 1.6066 (5.4); −0.0002 (6.0) 486.7 I-23 [00167] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5187 (1.4); 9.5022 (1.4); 8.3161 (0.6); 8.2513 (1.8); 8.2415 (2.9); 8.1992 (2.6); 8.0967 (2.4); 6.0822 (1.0); 6.0651 (1.6); 6.0480 (1.0); 4.6145 (1.7); 3.3284 (417.9); 2.6755 (2.0); 2.6711 (2.7); 2.6668 (2.0); 2.5244 (8.4); 2.5067 (353.6); 2.5022 (453.5); 2.4977 (328.4); 2.3364 (16.0); 2.3293 (3.6); 2.3246 (2.4); 2.0961 (0.4); 1.6281 (5.5); 1.6106 (5.5); 0.1464 (0.4); 0.0079 (2.9); −0.0001 (84.4); −0.0084 (3.2); −0.1494 (0.3) 511.8 I-24 [00168] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.2689 (1.5); 9.2523 (1.5); 8.2499 (1.7); 7.5854 (3.4); 7.5710 (2.5); 7.3013 (2.4); 6.0554 (1.1); 6.0381 (1.7); 6.0206 (1.1); 4.6138 (1.8); 3.3352 (53.8); 2.6767 (0.4); 2.6725 (0.6); 2.6680 (0.4); 2.5254 (1.8); 2.5077 (69.2); 2.5033 (91.2); 2.4989 (70.0); 2.3324 (16.0); 2.0880 (0.4); 2.0766 (2.9); 2.0673 (0.8); 2.0548 (1.3); 2.0423 (0.8); 2.0339 (0.7); 2.0212 (0.4); 1.6169 (5.9); 1.5994 (5.9); 1.0583 (0.6); 1.0477 (2.2); 1.0422 (2.5); 1.0316 (1.2); 1.0268 (2.3); 1.0214 (2.4); 1.0114 (0.8); 0.8155 (0.9); 0.8051 (2.3); 0.8010 (2.4); 0.7932 (2.4); 0.7886 (2.4); 0.7772 (0.8); 0.0078 (2.4); −0.0002 (60.4); −0.0083 (2.9) 533.8 I-25 [00169] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.2565 (1.4); 9.2393 (1.4); 8.1243 (6.6); 7.5817 (3.1); 7.5783 (2.4); 7.5671 (2.2); 7.2990 (2.0); 6.0468 (1.0); 6.0295 (1.6); 6.0122 (1.0); 3.3312 (61.5); 3.2415 (1.3); 3.0229 (1.3); 2.6762 (0.6); 2.6717 (0.8); 2.6673 (0.6); 2.5252 (2.6); 2.5117 (50.5); 2.5073 (99.4); 2.5028 (129.0); 2.4982 (95.3); 2.4939 (47.2); 2.3240 (16.0); 2.0739 (0.6); 2.0653 (0.6); 2.0530 (1.2); 2.0404 (0.7); 2.0323 (0.6); 2.0193 (0.3); 1.6119 (5.4); 1.5945 (5.4); 1.0576 (0.5); 1.0463 (2.0); 1.0408 (2.2); 1.0299 (1.0); 1.0254 (2.1); 1.0199 (2.1); 1.0094 (0.6); 0.8143 (0.8); 0.8040 (2.0); 0.8003 (2.0); 0.7984 (2.0); 0.7918 (2.1); 0.7877 (2.0); 0.7760 (0.7); 0.1458 (0.4); 0.0080 (3.7); −0.0002 (94.7); −0.0085 (3.8); −0.1496 (0.4) 508.9 I-26 [00170] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5374 (3.0); 9.5211 (3.0); 8.6712 (16.0); 8.3225 (13.0); 8.1528 (5.4); 7.9966 (4.2); 7.8010 (4.1); 7.3017 (2.3); 7.1635 (5.3); 7.0254 (2.6); 6.0744 (0.4); 6.0577 (2.1); 6.0408 (3.1); 6.0237 (2.1); 6.0065 (0.4); 3.3330 (78.9); 2.6772 (0.6); 2.6727 (0.8); 2.6681 (0.6); 2.5260 (2.6); 2.5125 (48.5); 2.5082 (94.8); 2.5036 (123.5); 2.4991 (91.0); 2.4947 (44.6); 2.3350 (0.5); 2.3305 (0.7); 2.3259 (0.5); 2.0766 (0.5); 1.6399 (12.3); 1.6224 (12.2); 0.1457 (0.4); 0.0079 (3.6); −0.0002 (84.5); −0.0085 (3.0); −0.1496 (0.4) 458.8 I-27 [00171] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3919 (2.2); 9.3754 (2.3); 8.6690 (11.3); 8.3158 (9.4); 8.0550 (4.3); 8.0517 (6.8); 8.0468 (16.0); 8.0433 (7.2); 6.0324 (0.3); 6.0151 (1.5); 5.9981 (2.4); 5.9810 (1.6); 5.9639 (0.4); 3.3298 (44.7); 2.6762 (0.8); 2.6718 (1.1); 2.6674 (0.8); 2.5252 (3.5); 2.5116 (66.2); 2.5073 (132.0); 2.5028 (173.7); 2.4983 (129.2); 2.4940 (64.6); 2.3342 (0.8); 2.3297 (1.0); 2.3253 (0.8); 2.0759 (1.1); 1.6115 (9.2); 1.5941 (9.2); 0.1461 (0.5); 0.0080 (4.2); −0.0001 (117.2); −0.0084 (4.6); −0.1495 (0.5) 482.6 I-28 [00172] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4547 (2.9); 9.4384 (3.0); 8.6683 (16.0); 8.3212 (13.1); 8.0183 (4.3); 8.0143 (6.6); 8.0103 (4.5); 7.8081 (4.4); 7.7896 (4.6); 7.7872 (4.6); 6.0511 (0.5); 6.0340 (2.1); 6.0170 (3.2); 6.0000 (2.1); 5.9827 (0.5); 3.3331 (206.0); 2.6766 (1.2); 2.6720 (1.6); 2.6675 (1.2); 2.5255 (4.9); 2.5120 (100.4); 2.5076 (200.6); 2.5031 (263.1); 2.4985 (193.9); 2.4940 (95.2); 2.3388 (0.6); 2.3345 (1.2); 2.3299 (1.6); 2.3254 (1.2); 2.3209 (0.6); 1.6269 (12.6); 1.6094 (12.5); 0.1460 (0.7); 0.0147 (0.5); 0.0081 (7.2); −0.0001 (196.8); −0.0084 (7.3); −0.0193 (0.5); −0.1495 (0.8) 442.7 I-29 [00173] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3647 (2.9); 9.3482 (3.0); 8.6683 (16.0); 8.3134 (12.9); 8.2010 (4.2); 8.1974 (7.9); 8.1939 (4.8); 8.1538 (4.6); 8.1497 (7.2); 8.1459 (4.2); 8.0348 (4.7); 8.0307 (7.0); 8.0268 (4.1); 6.0252 (0.4); 6.0081 (2.0); 5.9911 (3.0); 5.9741 (2.0); 5.9570 (0.4); 3.3342 (95.7); 2.6772 (0.5); 2.6727 (0.7); 2.6683 (0.5); 2.5261 (2.1); 2.5126 (42.3); 2.5083 (83.0); 2.5037 (107.9); 2.4992 (79.2); 2.4947 (38.6); 2.3349 (0.5); 2.3306 (0.7); 2.3262 (0.5); 2.0766 (2.3); 1.6070 (11.7); 1.5895 (11.7); 0.0080 (3.2); −0.0002 (76.2); −0.0085 (2.8) 528.5 I-30 [00174] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.2899 (2.9); 9.2735 (2.9); 8.6704 (16.0); 8.3120 (12.3); 7.5597 (6.4); 7.5563 (4.5); 7.5394 (4.4); 7.2978 (4.3); 6.0478 (0.4); 6.0311 (2.0); 6.0140 (3.0); 5.9969 (2.0); 5.9799 (0.4); 3.3329 (153.0); 2.6765 (0.9); 2.6721 (1.2); 2.6675 (0.9); 2.5255 (4.0); 2.5119 (75.1); 2.5075 (148.5); 2.5030 (194.0); 2.4985 (144.0); 2.4941 (71.3); 2.3344 (0.9); 2.3299 (1.2); 2.3253 (0.9); 2.0870 (0.6); 2.0747 (1.4); 2.0658 (1.4); 2.0535 (2.5); 2.0409 (1.4); 2.0325 (1.3); 2.0200 (0.7); 1.6245 (11.7); 1.6071 (11.7); 1.0577 (1.3); 1.0466 (4.2); 1.0411 (4.6); 1.0305 (2.2); 1.0256 (4.3); 1.0202 (4.4); 1.0099 (1.6); 0.8114 (1.8); 0.8008 (4.8); 0.7957 (4.8); 0.7884 (4.6); 0.7834 (4.9); 0.7720 (1.4); 0.1460 (0.5); 0.0080 (5.0); −0.0001 (131.4); −0.0084 (5.2); −0.0142 (0.5); −0.0150 (0.5); −0.0156 (0.5); −0.1495 (0.5) 448.8 I-31 [00175] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3514 (3.0); 9.3352 (3.1); 8.6694 (16.0); 8.3159 (13.1); 7.5557 (12.3); 7.5502 (12.8); 7.5280 (6.5); 7.3446 (13.6); 7.2513 (3.3); 7.2460 (5.8); 7.2407 (3.1); 7.1613 (6.8); 6.0568 (0.4); 6.0398 (2.1); 6.0229 (3.2); 6.0059 (2.1); 5.9885 (0.4); 3.3331 (60.4); 2.6768 (0.5); 2.6723 (0.7); 2.6678 (0.5); 2.5256 (2.2); 2.5121 (42.4); 2.5078 (83.4); 2.5033 (108.7); 2.4987 (80.1); 2.4944 (39.3); 2.3346 (0.5); 2.3301 (0.6); 2.3257 (0.5); 2.0761 (0.4); 1.6288 (12.3); 1.6113 (12.2); 0.0079 (1.9); −0.0002 (48.2); −0.0085 (1.6) 457.1 I-32 [00176] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6136 (3.3); 9.5973 (3.3); 8.6694 (16.0); 8.3304 (13.6); 8.3182 (0.6); 8.3057 (3.1); 8.3012 (6.7); 8.2966 (5.8); 8.2889 (5.3); 8.2856 (7.0); 8.2810 (3.5); 8.2578 (6.4); 6.0756 (0.5); 6.0587 (2.2); 6.0417 (3.4); 6.0247 (2.2); 6.0075 (0.5); 3.3326 (100.1); 2.6770 (0.8); 2.6725 (1.1); 2.6682 (0.8); 2.5258 (3.8); 2.5124 (68.6); 2.5081 (132.6); 2.5036 (171.4); 2.4991 (127.3); 2.4949 (64.0); 2.3349 (0.8); 2.3305 (1.0); 2.3260 (0.8); 2.0765 (11.0); 1.9098 (0.6); 1.6419 (13.3); 1.6245 (13.2); 0.0150 (0.4); 0.0079 (3.1); −0.0001 (71.6); −0.0083 (3.0) 485.1 I-33 [00177] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5537 (3.4); 9.5373 (3.4); 8.6753 (16.0); 8.3198 (13.7); 8.2460 (11.7); 7.9574 (5.4); 7.7117 (0.3); 7.3312 (4.8); 7.1926 (10.8); 7.1628 (0.5); 7.0541 (5.2); 6.0842 (0.5); 6.0673 (2.3); 6.0503 (3.5); 6.0331 (2.3); 6.0161 (0.5); 3.3349 (38.7); 2.6776 (0.4); 2.6732 (0.5); 2.6690 (0.4); 2.5086 (66.1); 2.5042 (84.8); 2.4997 (63.4); 2.3357 (0.4); 2.3308 (0.5); 2.3266 (0.4); 2.0772 (1.7); 1.6420 (13.5); 1.6246 (13.5); 0.0078 (1.6); −0.0002 (35.0); −0.0085 (1.6) 424.8 I-34 [00178] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4563 (3.9); 9.4400 (4.0); 8.6715 (15.9); 8.3167 (15.2); 7.9819 (7.5); 7.8138 (6.3); 7.5746 (6.3); 7.5536 (3.6); 7.3702 (7.4); 7.2635 (2.9); 7.1869 (3.7); 7.1250 (6.4); 6.9865 (3.1); 6.0701 (0.6); 6.0530 (2.7); 6.0361 (4.1); 6.0191 (2.7); 6.0019 (0.6); 3.3335 (62.7); 2.6769 (0.6); 2.6726 (0.8); 2.6686 (0.6); 2.5080 (96.2); 2.5037 (120.9); 2.4993 (91.2); 2.3305 (0.7); 2.3262 (0.5); 2.0764 (0.6); 1.6349 (16.0); 1.6174 (15.9); −0.0002 (37.8) 441.1 I-35 [00179] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.2057 (3.1); 9.1892 (3.1); 8.6716 (16.0); 8.3073 (12.8); 7.4430 (3.3); 7.4190 (6.8); 7.3762 (5.0); 7.2580 (6.8); 7.0773 (5.6); 7.0732 (6.9); 6.0441 (0.5); 6.0270 (2.1); 6.0100 (3.2); 5.9928 (2.1); 5.9759 (0.4); 3.3392 (57.6); 2.6768 (0.5); 2.6723 (0.6); 2.6679 (0.4); 2.5121 (40.5); 2.5079 (76.5); 2.5034 (97.5); 2.4988 (71.5); 2.4946 (35.3); 2.3346 (0.4); 2.3301 (0.6); 2.3258 (0.4); 2.0762 (2.1); 2.0339 (0.6); 2.0214 (1.3); 2.0128 (1.4); 2.0005 (2.6); 1.9879 (1.6); 1.9797 (1.4); 1.9670 (0.7); 1.6203 (12.4); 1.6028 (12.3); 1.0319 (1.2); 1.0209 (4.5); 1.0154 (4.9); 1.0048 (2.3); 1.0000 (4.6); 0.9945 (4.6); 0.9843 (1.4); 0.7874 (1.9); 0.7773 (4.7); 0.7741 (4.7); 0.7650 (4.7); 0.7609 (4.4); 0.7492 (1.5); 0.0079 (1.9); −0.0002 (40.8); −0.0084 (1.5) 431.2 I-36 [00180] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5764 (2.9); 9.5600 (3.0); 8.6713 (16.0); 8.3404 (4.3); 8.3367 (7.8); 8.3330 (4.9); 8.3262 (13.3); 8.3143 (0.4); 8.2503 (4.1); 8.2459 (6.5); 8.2418 (4.3); 8.1728 (4.6); 8.1685 (6.9); 8.1641 (3.8); 6.0838 (0.4); 6.0669 (2.0); 6.0498 (3.1); 6.0328 (2.0); 6.0154 (0.5); 3.3322 (34.7); 3.3200 (51.0); 2.6756 (0.8); 2.6711 (1.1); 2.6666 (0.8); 2.5245 (3.4); 2.5196 (5.4); 2.5110 (70.5); 2.5067 (141.7); 2.5021 (183.9); 2.4976 (130.8); 2.4932 (62.2); 2.3335 (0.8); 2.3290 (1.0); 2.3244 (0.8); 2.0742 (0.8); 1.6412 (12.2); 1.6238 (12.2); 0.0080 (0.5); −0.0002 (14.9); −0.0085 (0.5) 437.3 I-37 [00181] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6604 (3.6); 9.6440 (3.7); 8.6752 (16.0); 8.4692 (8.5); 8.3344 (13.9); 8.3180 (0.5); 8.1522 (5.7); 8.1048 (5.7); 6.1012 (0.6); 6.0841 (2.4); 6.0671 (3.6); 6.0500 (2.4); 6.0331 (0.6); 3.3976 (0.4); 3.3833 (1.1); 3.3653 (36.1); 3.3301 (47.0); 2.6764 (1.0); 2.6719 (1.4); 2.6677 (1.0); 2.5073 (172.3); 2.5029 (220.8); 2.4985 (168.4); 2.3341 (1.0); 2.3298 (1.4); 2.3254 (1.0); 2.0761 (0.4); 1.6528 (13.8); 1.6354 (13.8); 0.1459 (0.4); 0.0077 (4.1); −0.0001 (82.7); −0.0082 (4.3); −0.1496 (0.4) 486.8 I-38 [00182] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3456 (3.4); 9.3292 (3.5); 8.6652 (16.0); 8.3101 (13.3); 8.1214 (4.9); 8.1182 (8.3); 8.1149 (4.9); 7.7556 (4.0); 7.7510 (5.3); 7.7473 (4.1); 7.6181 (5.3); 7.5019 (3.5); 7.3183 (7.4); 7.1347 (3.7); 6.0378 (0.5); 6.0206 (2.2); 6.0036 (3.4); 5.9865 (2.2); 5.9694 (0.5); 3.3232 (85.9); 2.6760 (0.9); 2.6715 (1.2); 2.6669 (0.8); 2.5246 (3.8); 2.5112 (67.2); 2.5069 (131.6); 2.5024 (176.1); 2.4979 (131.9); 2.4936 (64.8); 2.3381 (0.4); 2.3337 (0.8); 2.3294 (1.1); 2.3248 (0.8); 2.0866 (1.2); 1.9555 (0.3); 1.6150 (12.9); 1.5975 (12.8); 1.2372 (1.2); 0.8542 (0.4); 0.1460 (0.9); 0.0080 (9.2); −0.0001 (200.8); −0.0083 (8.3); −0.0260 (0.3); −0.1495 (0.9) 517.0 I-39 [00183] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3737 (4.0); 9.3573 (4.0); 8.6669 (16.0); 8.3137 (14.4); 7.9720 (5.3); 7.9687 (8.5); 7.6564 (3.4); 7.6516 (7.2); 7.6474 (5.8); 7.6348 (6.7); 7.5294 (3.8); 7.3461 (7.7); 7.1628 (3.9); 6.0465 (0.6); 6.0293 (2.5); 6.0123 (3.8); 5.9952 (2.5); 5.9777 (0.6); 5.7556 (1.1); 3.8136 (0.4); 3.3276 (38.3); 2.6733 (0.4); 2.5086 (46.4); 2.5043 (61.0); 2.4999 (46.8); 2.3311 (0.4); 2.0877 (1.2); 1.6222 (14.5); 1.6048 (14.4); 1.2359 (0.3); 0.0076 (2.0); −0.0002 (34.6); −0.0082 (1.4) 471.0 I-40 [00184] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5203 (3.8); 9.5037 (3.8); 8.6157 (16.0); 8.3312 (4.8); 8.3276 (8.4); 8.3241 (5.1); 8.3149 (0.5); 8.3100 (0.4); 8.2992 (0.3); 8.2951 (0.4); 8.2393 (4.8); 8.2352 (7.6); 8.2311 (5.0); 8.1707 (5.1); 8.1665 (7.7); 8.1622 (4.1); 6.0293 (0.6); 6.0120 (2.5); 5.9949 (3.8); 5.9778 (2.5); 5.9606 (0.5); 5.7553 (5.7); 3.3671 (1.4); 3.3339 (42.5); 3.3250 (131.6); 2.6762 (0.7); 2.6718 (1.0); 2.6674 (0.7); 2.5116 (63.5); 2.5074 (120.9); 2.5030 (154.2); 2.4985 (112.2); 2.3341 (0.8); 2.3298 (1.0); 2.3253 (0.8); 2.1136 (0.7); 2.1016 (1.6); 2.0927 (1.8); 2.0809 (3.2); 2.0689 (2.0); 2.0602 (1.7); 2.0480 (0.9); 1.6017 (13.6); 1.5843 (13.4); 1.3657 (1.2); 1.3501 (1.2); 1.2455 (0.6); 1.2304 (1.1); 1.2143 (0.7); 1.0685 (0.4); 1.0551 (0.8); 1.0386 (5.0); 1.0347 (5.7); 1.0182 (5.0); 1.0138 (5.3); 477.0 0.9997 (1.1); 0.9864 (0.5); 0.9125 (0.6); 0.8937 (2.0); 0.8876 (3.0); 0.8813 (4.2); 0.8758 (4.9); 0.8456 (0.8); 0.8367 (0.6); −0.0001 (5.0) I-41 [00185] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4259 (3.5); 9.4096 (3.6); 8.6656 (16.0); 8.3203 (13.8); 8.1924 (8.5); 8.1000 (2.1); 8.0967 (2.3); 8.0937 (2.6); 8.0910 (2.2); 8.0790 (2.2); 8.0758 (2.5); 8.0728 (2.4); 8.0701 (2.1); 8.0149 (2.3); 8.0112 (2.6); 8.0055 (2.0); 7.9913 (2.4); 7.9877 (2.7); 7.9818 (2.0); 6.0593 (0.5); 6.0422 (2.4); 6.0252 (3.7); 6.0081 (2.4); 5.9911 (0.6); 5.7555 (2.5); 3.3550 (9.1); 2.6763 (0.6); 2.6720 (0.8); 2.6676 (0.6); 2.5250 (2.7); 2.5117 (51.0); 2.5075 (98.3); 2.5030 (126.2); 2.4985 (91.4); 2.4944 (45.7); 2.3343 (0.6); 2.3298 (0.8); 2.3256 (0.6); 1.6307 (14.7); 1.6133 (14.6); −0.0002 (1.4) 368.0 I-42 [00186] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5335 (3.1); 9.5168 (3.2); 9.2283 (0.8); 9.2114 (0.8); 8.6158 (16.0); 8.3429 (1.2); 8.3149 (0.9); 8.2926 (4.0); 8.2890 (7.2); 8.2854 (4.6); 8.2469 (4.2); 8.2424 (6.4); 8.2385 (4.0); 8.1417 (4.2); 8.1372 (6.5); 8.1330 (3.7); 7.9100 (0.9); 7.9057 (1.5); 7.9010 (1.0); 7.8410 (3.9); 7.8036 (0.8); 7.7842 (0.9); 7.6297 (0.6); 7.6100 (0.8); 7.6073 (0.8); 7.5247 (1.0); 7.5051 (1.4); 7.4853 (0.6); 6.0267 (0.5); 6.0099 (2.1); 5.9929 (3.2); 5.9757 (2.2); 5.9662 (0.8); 5.9585 (0.6); 5.9488 (0.9); 5.9320 (0.6); 5.9204 (0.4); 5.9029 (0.4); 5.7551 (8.4); 3.3716 (0.4); 3.3233 (285.8); 3.0526 (0.6); 3.0405 (1.4); 3.0328 (1.5); 3.0212 (2.8); 3.0093 (1.6); 3.0014 (1.5); 2.9893 (0.7); 2.6899 (0.8); 2.6755 (1.9); 2.6710 (2.6); 2.6666 (1.9); 2.5241 (8.1); 2.5106 (160.0); 2.5065 (308.5); 2.5021 503.0 (396.9); 2.4976 (288.2); 2.4934 (143.6); 2.3334 (1.8); 2.3289 (2.5); 2.3243 (1.8); 2.1146 (0.7); 2.1027 (1.5); 2.0937 (1.9); 2.0820 (3.0); 2.0705 (2.0); 2.0612 (1.8); 2.0495 (0.9); 1.7849 (1.1); 1.7674 (1.1); 1.6022 (11.6); 1.5848 (11.8); 1.5774 (4.5); 1.5595 (3.2); 1.3417 (0.5); 1.2300 (0.7); 1.2182 (0.7); 1.2046 (1.9); 1.1962 (4.1); 1.1927 (3.8); 1.1851 (4.0); 1.1759 (2.7); 1.1669 (1.0); 1.1548 (0.7); 1.1429 (0.7); 1.1289 (0.8); 1.1205 (1.2); 1.1079 (4.0); 1.1008 (3.5); 1.0885 (3.8); 1.0826 (2.9); 1.0670 (1.1); 1.0568 (1.0); 1.0386 (4.9); 1.0349 (5.7); 1.0182 (4.8); 1.0138 (5.2); 1.0059 (2.0); 0.9990 (1.1); 0.9856 (0.6); 0.9124 (0.9); 0.9013 (1.2); 0.8887 (2.6); 0.8774 (4.4); 0.8714 (3.7); 0.8670 (3.5); 0.8561 (2.2); 0.8435 (1.1); 0.8212 (0.4); −0.0001 (4.7) I-43 [00187] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3487 (3.2); 9.3322 (3.2); 8.6687 (16.0); 8.3111 (12.7); 7.9735 (4.3); 7.9695 (7.0); 7.9655 (4.2); 7.7223 (6.6); 7.6032 (4.0); 7.5994 (6.2); 6.0516 (0.5); 6.0343 (2.2); 6.0173 (3.2); 6.0002 (2.1); 5.9830 (0.5); 5.7554 (1.0); 3.3253 (256.4); 2.6756 (1.0); 2.6712 (1.4); 2.6668 (1.0); 2.6622 (0.5); 2.5243 (5.3); 2.5110 (89.1); 2.5067 (170.2); 2.5023 (217.4); 2.4977 (156.1); 2.4933 (75.7); 2.3334 (1.0); 2.3291 (1.4); 2.3246 (1.0); 2.0744 (0.4); 1.6210 (12.8); 1.6035 (12.7); 1.5740 (1.2); 1.5579 (3.6); 1.5537 (3.7); 1.5391 (1.4); 1.5251 (1.1); 1.5091 (3.3); 1.5048 (3.6); 1.4904 (1.5); 1.3009 (1.3); 1.2858 (3.9); 1.2800 (4.3); 1.2628 (4.5); 1.2580 (3.4); 1.2420 (1.0); −0.0002 (3.2) 463.0 I-44 [00188] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.2877 (3.3); 9.2713 (3.3); 8.6711 (16.0); 8.3150 (0.7); 8.3059 (13.2); 7.8100 (5.5); 7.6685 (5.4); 7.4620 (5.4); 7.1630 (2.5); 7.0236 (5.7); 6.8843 (2.8); 6.0571 (0.5); 6.0398 (2.2); 6.0227 (3.4); 6.0056 (2.2); 5.9883 (0.5); 5.7555 (3.0); 3.3259 (109.6); 2.6762 (0.6); 2.6717 (0.9); 2.6672 (0.6); 2.5249 (2.7); 2.5115 (53.2); 2.5072 (102.1); 2.5027 (130.0); 2.4982 (93.0); 2.4938 (44.9); 2.3340 (0.6); 2.3295 (0.8); 2.3250 (0.6); 2.0920 (0.7); 2.0793 (1.4); 2.0709 (1.6); 2.0584 (2.9); 2.0459 (1.7); 2.0376 (1.5); 2.0249 (0.8); 1.6265 (13.5); 1.6090 (13.4); 1.0489 (1.3); 1.0379 (5.0); 1.0325 (5.3); 1.0220 (2.4); 1.0170 (5.1); 1.0116 (5.1); 1.0015 (1.6); 0.7907 (2.1); 0.7806 (4.9); 0.7772 (4.9); 0.7751 (4.8); 0.7682 (5.0); 0.7642 (4.7); 0.7525 (1.8); 0.7373 (0.4); −0.0001 (1.7) 415.1 I-45 [00189] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.2999 (1.4); 9.2915 (1.6); 9.2837 (1.6); 9.2754 (1.5); 8.6676 (7.4); 8.3084 (7.0); 7.9604 (3.5); 7.9560 (3.6); 7.7404 (2.5); 7.7298 (2.5); 7.6960 (4.4); 6.0466 (0.3); 6.0293 (1.5); 6.0122 (2.3); 5.9951 (1.5); 5.9790 (0.4); 5.7554 (16.0); 3.3244 (39.9); 3.1548 (0.6); 3.1337 (0.7); 3.1243 (1.2); 3.1033 (1.2); 3.0942 (0.8); 3.0723 (0.6); 2.6760 (0.3); 2.6716 (0.5); 2.6669 (0.4); 2.5112 (28.9); 2.5071 (55.6); 2.5027 (71.8); 2.4983 (53.0); 2.4941 (27.0); 2.3338 (0.3); 2.3297 (0.4); 2.3247 (0.3); 2.1679 (0.3); 2.1565 (0.5); 2.1475 (0.9); 2.1387 (0.8); 2.1258 (0.9); 2.1153 (0.8); 2.1058 (0.6); 2.0932 (0.5); 2.0852 (0.3); 2.0770 (0.4); 2.0609 (0.5); 2.0457 (0.9); 2.0309 (1.0); 2.0116 (0.7); 1.9998 (0.6); 1.6204 (9.6); 1.6030 (9.5); −0.0002 (1.1) 481.0 I-46 [00190] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5933 (3.6); 9.5769 (3.6); 9.2836 (1.0); 9.2671 (1.0); 8.6726 (16.0); 8.3288 (12.9); 8.3060 (11.2); 8.2636 (4.9); 8.2592 (7.4); 8.2555 (4.7); 8.1449 (4.8); 8.1405 (7.3); 8.1364 (4.2); 7.9263 (1.3); 7.9222 (2.0); 7.9179 (1.3); 7.8159 (1.1); 7.7964 (1.3); 7.6318 (0.8); 7.6292 (0.7); 7.6119 (1.1); 7.6091 (1.1); 7.5241 (1.2); 7.5044 (1.9); 7.4846 (0.8); 6.0858 (0.5); 6.0690 (2.3); 6.0520 (3.5); 6.0350 (2.4); 6.0268 (1.0); 6.0174 (0.7); 6.0094 (1.2); 5.9924 (0.7); 5.7555 (13.0); 3.3255 (89.5); 3.0568 (0.7); 3.0448 (1.6); 3.0371 (1.8); 3.0254 (3.2); 3.0135 (1.8); 3.0057 (1.6); 2.9937 (0.8); 2.6765 (0.6); 2.6722 (0.8); 2.6676 (0.6); 2.5074 (99.2); 2.5031 (126.1); 2.4987 (93.8); 2.3343 (0.6); 2.3298 (0.8); 2.3257 (0.6); 1.6440 463.0 (13.5); 1.6265 (13.9); 1.6179 (5.8); 1.6002 (4.5); 1.4263 (0.4); 1.4089 (0.5); 1.3418 (0.8); 1.2455 (0.9); 1.2289 (2.0); 1.2108 (2.0); 1.1927 (5.2); 1.1846 (5.2); 1.1743 (2.8); 1.1571 (0.9); 1.1425 (0.9); 1.1280 (0.8); 1.1191 (1.4); 1.1066 (4.7); 1.0998 (4.4); 1.0869 (4.7); 1.0812 (3.8); 1.0656 (0.8); −0.0002 (1.9) I-47 [00191] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4419 (3.4); 9.4255 (3.4); 8.6709 (13.8); 8.3169 (11.9); 8.1814 (6.2); 8.0261 (6.2); 7.9431 (5.9); 6.0646 (0.5); 6.0476 (2.1); 6.0306 (3.3); 6.0136 (2.2); 5.9966 (0.5); 5.7556 (6.7); 3.3229 (69.9); 2.6715 (1.0); 2.6670 (0.8); 2.5066 (130.4); 2.5025 (161.4); 2.4982 (118.5); 2.3292 (1.0); 2.3249 (0.8); 2.0532 (7.3); 2.0057 (16.0); 1.9580 (8.1); 1.6306 (12.8); 1.6132 (12.8); −0.0002 (4.5) 469.1 I-48 [00192] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5946 (4.0); 9.5779 (4.0); 8.6153 (16.0); 8.5849 (1.8); 8.4475 (8.8); 8.3154 (0.5); 8.2227 (0.6); 8.1311 (6.1); 8.0993 (6.0); 6.8369 (0.4); 6.8163 (0.4); 6.0412 (0.6); 6.0248 (2.6); 6.0077 (4.0); 5.9908 (2.6); 5.9733 (0.6); 5.6194 (0.3); 3.3641 (39.5); 3.3240 (62.4); 2.9455 (0.8); 2.6715 (2.0); 2.5067 (238.9); 2.5024 (302.5); 2.4982 (225.4); 2.3292 (1.9); 2.1224 (0.5); 2.1149 (0.8); 2.1027 (1.8); 2.0937 (2.1); 2.0821 (3.6); 2.0702 (2.3); 2.0615 (2.0); 2.0493 (1.0); 1.6123 (14.4); 1.5948 (14.4); 1.3599 (1.5); 1.3424 (1.6); 1.2351 (0.5); 1.0697 (0.5); 1.0551 (1.2); 1.0353 (6.8); 1.0179 (6.0); 1.0145 (6.0); 0.9991 (1.0); 0.9854 (0.6); 0.8872 (3.4); 0.8756 (5.2); 0.8434 (0.9); 0.8349 (0.7); −0.0002 (1.0) 527.0 I-49 [00193] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4303 (3.1); 9.4139 (3.1); 8.6707 (16.0); 8.3153 (12.8); 7.9541 (5.5); 7.8704 (2.1); 7.8679 (2.1); 7.8466 (2.1); 7.8442 (2.1); 7.6648 (2.1); 7.6431 (2.1); 7.2524 (2.5); 7.1139 (5.4); 6.9754 (2.6); 6.0667 (0.5); 6.0496 (2.2); 6.0326 (3.3); 6.0155 (2.2); 5.9982 (0.5); 3.3338 (25.7); 2.5288 (0.6); 2.5153 (11.6); 2.5110 (22.7); 2.5065 (29.2); 2.5019 (21.0); 2.4975 (10.2); 2.0781 (3.0); 1.6357 (13.0); 1.6182 (12.8); 1.3396 (0.4); 0.0078 (1.9); −0.0002 (41.1); −0.0085 (1.6) 393.1 I-50 [00194] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5938 (3.1); 9.5775 (3.2); 8.6717 (16.0); 8.3271 (13.1); 8.3147 (0.8); 8.2747 (4.4); 8.2712 (7.7); 8.2677 (4.6); 7.9729 (4.9); 7.9691 (3.8); 7.8483 (3.8); 7.8439 (5.0); 7.8393 (3.5); 7.6322 (3.3); 7.4496 (7.0); 7.2669 (3.4); 6.0963 (0.5); 6.0791 (2.1); 6.0621 (3.2); 6.0450 (2.1); 6.0274 (0.4); 5.7543 (3.5); 3.3226 (132.0); 3.0212 (0.6); 3.0093 (1.4); 3.0016 (1.6); 2.9950 (2.8); 2.9899 (3.0); 2.9816 (1.2); 2.9779 (1.6); 2.9701 (1.5); 2.9581 (0.7); 2.8913 (0.9); 2.7317 (0.8); 2.6755 (1.3); 2.6710 (1.7); 2.6665 (1.3); 2.5243 (6.5); 2.5111 (102.8); 2.5067 (202.5); 2.5021 (263.0); 2.4976 (188.3); 2.4931 (90.6); 2.3335 (1.2); 2.3289 (1.7); 2.3244 (1.2); 2.3198 (0.6); 1.6500 (12.7); 1.6325 (12.6); 1.2341 (0.5); 1.2266 (0.5); 1.2007 (1.9); 1.1931 (4.1); 1.1893 (4.1); 1.1821 (4.4); 1.1721 (2.4); 1.1651 (1.1); 1.1592 (0.7); 1.1524(0.7); 1.1399 (0.8); 1.1266 (0.8); 1.1181 (1.2); 1.1054 (4.1); 495.1 1.0985 (3.6); 1.0856 (3.8); 1.0800 (3.0); 1.0640 (0.7); 0.1458 (1.8); 0.0079 (19.0); −0.0002 (414.7); −0.0085 (16.4); −0.1497 (1.8) I-51 [00195] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6902 (2.3); 9.6738 (2.3); 8.6762 (8.8); 8.5414 (4.1); 8.4181 (4.0); 8.3307 (8.3); 8.2532 (4.0); 7.3880 (1.6); 7.2498 (3.6); 7.1118 (1.8); 6.1156 (0.4); 6.0983 (1.5); 6.0813 (2.3); 6.0642 (1.6); 6.0471 (0.4); 5.7546 (16.0); 3.3274 (15.9); 3.0403 (0.5); 3.0283 (1.0); 3.0207 (1.1); 3.0090 (2.0); 2.9976 (1.4); 2.9893 (1.1); 2.9772 (0.5); 2.8930 (0.6); 2.7337 (0.5); 2.5088 (28.1); 2.5046 (35.4); 2.5002 (25.9); 1.6607 (9.0); 1.6433 (9.0); 1.2340 (1.3); 1.2222 (0.6); 1.2079 (1.5); 1.1999 (3.2); 1.1964 (3.1); 1.1895 (3.3); 1.1801 (2.1); 1.1716 (1.0); 1.1593 (0.6); 1.1497 (0.6); 1.1336 (0.7); 1.1278 (0.9); 1.1152 (3.3); 1.1083 (2.8); 1.0956 (3.1); 1.0896 (2.4); 1.0731 (0.6); −0.0002 (42.9); −0.0084 (2.2) 479.1 I-52 [00196] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3662 (2.8); 9.3498 (2.8); 8.6694 (13.6); 8.3152 (11.3); 8.3060 (0.4); 8.1563 (0.5); 7.8711 (3.8); 7.8672 (5.9); 7.8630 (3.8); 7.7622 (3.9); 7.7583 (6.2); 7.7544 (3.6); 7.5453 (3.9); 7.5407 (6.6); 7.5361 (3.5); 7.3964 (0.4); 6.0554 (0.4); 6.0382 (1.9); 6.0211 (2.8); 6.0041 (1.9); 5.9868 (0.4); 3.3276 (34.2); 2.6767 (0.4); 2.6724 (0.5); 2.6678 (0.4); 2.5256 (1.9); 2.5122 (31.0); 2.5079 (59.5); 2.5034 (75.7); 2.4989 (54.0); 2.4945 (26.0); 2.3349 (0.4); 2.3304 (0.5); 2.3258 (0.4); 2.0752 (5.2); 1.8253 (2.2); 1.8125 (6.6); 1.8051 (7.0); 1.7936 (3.1); 1.7544 (0.4); 1.6877 (0.4); 1.6491 (3.4); 1.6367 (7.8); 1.6285 (16.0); 1.6104 (11.3); 1.1198 (0.4); 0.1460 (0.5); 0.0078 (4.9); −0.0002 (102.5); −0.0085 (4.1); −0.1495 (0.5) 424.1 I-53 [00197] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3258 (3.3); 9.3095 (3.4); 8.6665 (16.0); 8.3122 (13.6); 7.6132 (2.0); 7.6099 (2.5); 7.6081 (2.6); 7.6046 (2.2); 7.5900 (2.1); 7.5867 (2.7); 7.5814 (2.2); 7.5263 (7.2); 7.5219 (5.6); 7.3781 (1.8); 7.3725 (3.1); 7.3670 (1.7); 7.3543 (2.0); 7.3486 (3.5); 7.3433 (9.0); 7.1601 (3.8); 6.0476 (0.5); 6.0305 (2.3); 6.0135 (3.5); 5.9964 (2.3); 5.9790 (0.5); 3.3247 (119.8); 2.6758 (0.7); 2.6713 (1.0); 2.6669 (0.7); 2.5246 (3.4); 2.5113 (60.7); 2.5069 (120.6); 2.5024 (157.1); 2.4979 (113.5); 2.4936 (55.7); 2.3337 (0.7); 2.3292 (1.0); 2.3248 (0.7); 1.6243 (14.1); 1.6069 (14.0); 0.1459 (0.9); 0.0078 (9.2); −0.0002 (213.5); −0.0086 (8.4); −0.1496 (1.0) 409.1 I-54 [00198] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5769 (3.0); 9.5605 (3.1); 8.6724 (16.0); 8.3266 (12.8); 8.3149 (0.5); 8.3049 (4.4); 8.3014 (7.5); 8.2978 (4.4); 7.9666 (3.5); 7.9619 (4.8); 7.9582 (3.8); 7.8881 (3.8); 7.8839 (4.9); 7.8790 (3.3); 7.6202 (3.3); 7.4376 (6.9); 7.2550 (3.5); 6.0960 (0.4); 6.0790 (2.0); 6.0620 (3.1); 6.0450 (2.0); 6.0275 (0.5); 4.0560 (0.3); 4.0382 (1.0); 4.0204 (1.1); 4.0026 (0.4); 3.3234 (51.5); 2.6761 (0.5); 2.6717 (0.6); 2.6671 (0.5); 2.5250 (2.2); 2.5116 (39.0); 2.5072 (76.5); 2.5027 (98.7); 2.4981 (70.9); 2.4936 (34.4); 2.3340 (0.4); 2.3294 (0.6); 2.3250 (0.4); 2.0117 (0.8); 1.9892 (4.6); 1.6484 (12.2); 1.6310 (12.1); 1.4092 (0.3); 1.3419 (0.4); 1.3358 (0.4); 1.2342 (0.4); 1.1933 (1.3); 1.1755 (2.6); 1.1577 (1.2); 0.8887 (0.9); 0.8719 (0.9); 0.0079 (1.3); −0.0002 (30.7); −0.0084 (1.2) 469.1 I-55 [00199] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.7411 (2.0); 9.7248 (2.0); 8.6856 (2.7); 8.6816 (4.6); 8.6777 (2.8); 8.6563 (9.9); 8.5229 (3.9); 8.4981 (3.6); 8.3321 (8.5); 6.0756 (1.3); 6.0588 (2.0); 6.0418 (1.3); 3.5407 (0.4); 3.5152 (0.7); 3.3934 (1013.9); 3.2674 (0.4); 2.6810 (0.5); 2.6765 (0.7); 2.6722 (0.5); 2.5296 (2.3); 2.5164 (45.5); 2.5121 (89.0); 2.5076 (114.6); 2.5030 (82.0); 2.4986 (39.5); 2.3388 (0.5); 2.3344 (0.7); 2.3298 (0.5); 2.0728 (16.0); 1.9898 (0.5); 1.6505 (8.0); 1.6331 (8.0); 0.1460 (0.8); 0.0227 (0.4); 0.0078 (8.5); −0.0002 (170.7); −0.0085 (6.1); −0.1496 (0.8) 534.9 I-56 [00200] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6129 (3.0); 9.5966 (3.1); 8.6841 (0.5); 8.6803 (0.4); 8.6653 (16.0); 8.5265 (0.3); 8.3361 (1.1); 8.3284 (12.8); 8.3159 (0.4); 8.2982 (5.6); 8.0539 (5.3); 8.0357 (4.3); 8.0320 (6.1); 6.0921 (0.4); 6.0749 (2.0); 6.0578 (3.1); 6.0408 (2.0); 6.0233 (0.4); 3.3263 (124.5); 2.6769 (0.7); 2.6723 (0.9); 2.6681 (0.7); 2.5256 (3.2); 2.5124 (56.5); 2.5080 (109.2); 2.5035 (139.5); 2.4989 (98.9); 2.4945 (47.0); 2.3348 (0.6); 2.3303 (0.9); 2.3255 (0.6); 2.3098 (0.6); 2.2974 (1.2); 2.2890 (1.4); 2.2765 (2.5); 2.2642 (1.4); 2.2557 (1.3); 2.2432 (0.7); 2.0754 (8.1); 1.9896 (0.6); 1.6499 (12.5); 1.6324 (12.4); 1.1759 (0.4); 1.1466 (1.5); 1.1354 (3.8); 1.1298 (4.2); 1.1191 (2.5); 1.1145 (4.0); 1.1089 (4.0); 1.0984 (1.7); 0.9109 (1.8); 0.8997 (4.8); 0.8950 (4.6); 0.8878 (4.3); 0.8828 (5.0); 0.8711 (1.4); 0.1461 (0.8); 0.0080 (8.5); −0.0001 (172.4); −0.0084 497.1 (6.6); −0.0165 (0.5); −0.0172 (0.5); −0.0223 (0.3); −0.1494 (0.8) I-57 [00201] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4512 (3.0); 9.4349 (3.1); 8.6669 (16.0); 8.3196 (12.4); 8.1514 (4.2); 8.1476 (6.9); 8.1438 (4.3); 7.9069 (4.2); 7.8170 (4.0); 7.8145 (4.4); 7.8122 (3.8); 6.0527 (0.4); 6.0354 (2.0); 6.0184 (3.1); 6.0013 (2.0); 5.9840 (0.5); 3.3281 (40.8); 2.6735 (0.4); 2.5269 (1.5); 2.5135 (25.3); 2.5091 (49.8); 2.5046 (64.3); 2.5000 (45.7); 2.4956 (21.8); 2.3314 (0.4); 2.0765 (0.4); 1.6276 (12.3); 1.6101 (12.2); 0.1459 (0.3); 0.0125 (0.7); 0.0081 (3.6); −0.0002 (85.5); −0.0070 (2.2); −0.0085 (3.2); −0.0150 (0.4); −0.0156 (0.4); −0.1497 (0.4) 489.0 I-58 [00202] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4505 (3.9); 9.4341 (4.0); 8.6668 (16.0); 8.3700 (4.4); 8.3661 (7.8); 8.3624 (6.1); 8.3441 (5.9); 8.3402 (8.8); 8.3360 (5.2); 8.3211 (14.3); 8.2931 (6.2); 8.2898 (9.2); 6.0554 (0.6); 6.0385 (2.6); 6.0215 (3.9); 6.0045 (2.6); 5.9869 (0.6); 3.3278 (51.0); 2.6777 (0.4); 2.6735 (0.5); 2.5088 (55.7); 2.5044 (70.2); 2.5000 (52.1); 2.3311 (0.4); 2.3267 (0.3); 2.0763 (5.2); 1.6263 (15.4); 1.6089 (15.1); 0.1461 (0.3); 0.0076 (4.5); −0.0002 (69.1); −0.0081 (3.9) 430.0 I-59 [00203] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3903 (3.2); 9.3739 (3.2); 8.6668 (16.0); 8.3145 (13.4); 8.2088 (1.0); 8.0225 (4.3); 8.0186 (7.6); 8.0147 (4.9); 7.9448 (3.6); 7.9402 (7.4); 7.9358 (4.4); 7.9155 (5.4); 7.9115 (7.0); 7.9073 (3.8); 6.0374 (0.5); 6.0202 (2.2); 6.0032 (3.3); 5.9861 (2.2); 5.9689 (0.5); 3.3515 (4.3); 2.5274 (1.0); 2.5142 (20.1); 2.5098 (39.5); 2.5053 (51.1); 2.5007 (36.4); 2.4963 (17.5); 2.3321 (0.3); 2.0767 (8.2); 1.6166 (13.1); 1.5992 (13.0); 0.0077 (2.6); −0.0002 (56.2); −0.0086 (2.1) 461.1 I-60 [00204] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.7441 (3.5); 9.7278 (3.6); 8.6641 (16.0); 8.5558 (4.4); 8.5518 (7.4); 8.5477 (5.0); 8.5022 (6.9); 8.4308 (6.1); 8.3366 (14.1); 8.3159 (0.3); 6.0960 (0.5); 6.0790 (2.3); 6.0621 (3.6); 6.0450 (2.3); 6.0278 (0.5); 3.3261 (166.8); 2.6764 (0.9); 2.6721 (1.2); 2.6676 (0.9); 2.5250 (4.1); 2.5117 (78.1); 2.5075 (150.0); 2.5031 (191.8); 2.4986 (137.6); 2.4945 (67.4); 2.3343 (0.9); 2.3299 (1.2); 2.3256 (0.8); 2.0752 (2.6); 1.9895 (1.3); 1.6516 (13.9); 1.6342 (13.9); 1.1934 (0.4); 1.1757 (0.7); 1.1580 (0.4); 0.1462 (0.5); 0.0079 (5.2); −0.0001 (113.7); −0.0080 (4.5); −0.1495 (0.5) 491.1 I-61 [00205] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6721 (3.3); 9.6557 (3.3); 8.6724 (16.0); 8.4415 (4.4); 8.4380 (7.7); 8.4345 (4.6); 8.3339 (13.6); 8.3154 (1.0); 8.1643 (4.6); 8.0759 (4.6); 6.1016 (0.5); 6.0843 (2.2); 6.0676 (3.2); 6.0504 (2.1); 6.0336 (0.5); 3.3237 (300.2); 3.0740 (0.6); 3.0619 (1.5); 3.0540 (1.6); 3.0425 (3.0); 3.0304 (1.7); 3.0228 (1.6); 3.0108 (0.7); 2.6755 (2.3); 2.6710 (3.1); 2.6665 (2.3); 2.5242 (10.7); 2.5109 (186.4); 2.5065 (370.0); 2.5020 (482.0); 2.4975 (346.9); 2.4931 (168.6); 2.3332 (2.2); 2.3288 (3.0); 2.3244 (2.2); 2.0743 (1.2); 1.6546 (12.9); 1.6372 (12.8); 1.2454 (0.4); 1.2337 (1.0); 1.2198 (1.9); 1.2121 (4.0); 1.2082 (4.1); 1.2012 (4.3); 1.1912 (2.4); 1.1839 (0.8); 1.1718 (0.7); 1.1562 (0.6); 1.1410 (0.5); 1.1324 (1.2); 1.1193 (4.2); 1.1127 (3.7); 1.0996 (4.0); 1.0937 (3.1); 1.0777 (0.6); 0.1458 (1.5); 0.0077 (13.8); −0.0002 (329.3); −0.0085 (12.9); −0.1497 (1.5) 513.1 I-62 [00206] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6622 (2.8); 9.6458 (2.8); 8.6695 (13.4); 8.4299 (3.7); 8.4264 (6.4); 8.4230 (3.8); 8.3338 (10.9); 8.3154 (0.7); 8.1723 (3.9); 8.0516 (4.0); 6.1002 (0.4); 6.0831 (1.8); 6.0661 (2.8); 6.0492 (1.8); 6.0324 (0.4); 3.4855 (2.0); 3.4670 (6.7); 3.4486 (6.8); 3.4303 (2.1); 3.3254 (375.7); 2.6756 (1.7); 2.6711 (2.2); 2.6667 (1.7); 2.5243 (8.2); 2.5110 (138.2); 2.5067 (271.5); 2.5022 (352.7); 2.4977 (253.5); 2.4934 (123.3); 2.3336 (1.6); 2.3290 (2.2); 2.3246 (1.7); 2.0744 (0.4); 1.6536 (10.8); 1.6361 (10.7); 1.1483 (7.2); 1.1300 (16.0); 1.1116 (6.9); 0.1460 (1.0); 0.0080 (8.9); −0.0001 (214.3); −0.0084 (8.5); −0.1496 (1.0) 501.1 I-63 [00207] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6721 (3.0); 9.6557 (3.0); 9.3403 (0.4); 9.3232 (0.4); 8.6662 (13.8); 8.3975 (6.8); 8.3342 (11.9); 8.3152 (2.0); 8.3087 (1.3); 8.1965 (4.4); 8.0123 (4.6); 7.9017 (0.3); 7.8162 (0.5); 7.6236 (0.5); 7.6056 (0.3); 7.5769 (0.3); 6.0992 (0.5); 6.0819 (1.9); 6.0651 (2.9); 6.0481 (2.0); 6.0311 (0.5); 6.0219 (0.4); 3.8817 (0.7); 3.6497 (0.8); 3.6330 (2.1); 3.6161 (3.0); 3.5990 (2.2); 3.5820 (0.8); 3.3225 (407.2); 2.6751 (5.7); 2.6706 (7.6); 2.6661 (5.7); 2.6198 (0.6); 2.6051 (0.6); 2.5856 (0.8); 2.5236 (33.0); 2.5102 (501.7); 2.5061 (953.8); 2.5017 (1210.2); 2.4972 (875.0); 2.4930 (434.6); 2.3330 (5.5); 2.3284 (7.5); 2.3241 (5.4); 2.0741 (1.5); 1.6541 (11.6); 1.6367 (11.6); 1.6099 (1.4); 1.1974 (14.7); 1.1876 (16.0); 1.1804 (15.6); 1.1706 (14.5); 0.1456 (1.5); 0.0074 (14.8); −0.0003 (336.7); −0.0085 (14.2); −0.1497 (1.5) 515.0 I-64 [00208] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6730 (2.9); 9.6567 (2.9); 9.3418 (0.3); 9.3238 (0.3); 8.6667 (14.7); 8.4010 (3.9); 8.3976 (6.8); 8.3349 (11.9); 8.3157 (2.4); 8.3096 (1.2); 8.1965 (4.3); 8.0125 (4.2); 7.9016 (0.4); 7.8169 (0.4); 7.6248 (0.5); 7.6061 (0.4); 7.5782 (0.4); 6.0985 (0.5); 6.0821 (2.0); 6.0651 (3.0); 6.0480 (2.0); 6.0312 (0.5); 6.0211 (0.3); 3.6502 (0.8); 3.6336 (2.1); 3.6167 (3.0); 3.5993 (2.3); 3.5827 (0.9); 3.3239 (760.3); 2.6754 (5.8); 2.6709 (7.9); 2.6665 (5.9); 2.5242 (27.8); 2.5108 (481.6); 2.5065 (960.7); 2.5020 (1254.2); 2.4975 (907.0); 2.4931 (443.9); 2.3926 (0.3); 2.3333 (5.6); 2.3287 (7.7); 2.3244 (5.8); 2.0743 (2.4); 1.6543 (11.5); 1.6369 (11.6); 1.6100 (1.3); 1.2372 (0.4); 1.1976 (14.8); 1.1877 (16.0); 1.1806 (15.7); 1.1708 (14.6); 0.1462 (3.1); 0.0080 (30.0); −0.0001 (748.2); −0.0084 (27.8); −0.0390 (0.5); −0.0531 (0.3); −0.1495 (3.3) 507.2 I-65 [00209] .sup.1H-NMR(600.1 MHz, CD3CN lowT): δ = 8.3640 (6.6); 8.2116 (2.7); 8.1688 (1.1); 8.1570 (1.1); 8.0257 (5.6); 8.0207 (0.7); 7.9231 (7.2); 6.1964 (1.1); 6.1846 (1.7); 6.1729 (1.1); 3.2685 (16.0); 3.0526 (15.0); 2.2987 (10.2); 2.2670 (0.8); 2.0726 (0.4); 1.9777 (1.0); 1.9699 (23.4); 1.9658 (45.4); 1.9617 (65.8); 1.9576 (46.3); 1.9535 (23.9); 1.8466 (0.4); 1.6791 (7.3); 1.6674 (7.3); 0.0053 (2.5); −0.0001 (66.4); −0.0055 (2.9) 517.1 I-66 [00210] .sup.1H-NMR 400.2 MHz, d.sub.6-DMSO): δ = 9.4928 (1.5); 9.4759 (1.5); 8.7792 (1.6); 8.7702 (1.6); 8.2232 (2.9); 8.2034 (6.2); 8.1767 (2.8); 8.0964 (2.6); 6.0428 (1.0); 6.0256 (1.6); 6.0083 (1.0); 3.3390 (115.4); 2.8175 (0.5); 2.8083 (0.8); 2.7995 (1.1); 2.7901 (1.1); 2.7810 (0.8); 2.7722 (0.5); 2.6768 (0.6); 2.6724 (0.8); 2.6679 (0.6); 2.5257 (2.6); 2.5079 (101.8); 2.5035 (130.9); 2.4990 (97.4); 2.3274 (16.0); 2.0768 (3.2); 1.6073 (5.6); 1.5900 (5.7); 0.7569 (0.6); 0.7434 (1.9); 0.7390 (2.5); 0.7266 (2.4); 0.7210 (2.0); 0.7095 (0.8); 0.5936 (0.8); 0.5827 (2.6); 0.5763 (2.5); 0.5675 (2.1); 0.5550 (0.6); 0.1459 (0.6); 0.0078 (5.3); −0.0002 (125.7); −0.0085 (5.4); −0.1498 (0.6) 498.8 I-67 [00211] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.5004 (1.8); 9.4833 (1.8); 8.8934 (1.0); 8.8795 (1.8); 8.8660 (1.0); 8.2767 (5.7); 8.2283 (3.4); 8.1834 (3.5); 8.0984 (3.2); 6.0571 (1.2); 6.0399 (1.8); 6.0226 (1.2); 3.3394 (213.6); 3.1534 (2.3); 3.1377 (3.8); 3.1224 (2.3); 2.6719 (1.4); 2.5029 (224.6); 2.3294 (16.0); 1.6150 (6.3); 1.5976 (6.3); 1.0361 (0.7); 1.0315 (0.7); 1.0189 (1.0); 1.0079 (0.8); 1.0012 (0.8); 0.9884 (0.4); 0.4873 (0.8); 0.4735 (3.0); 0.4564 (2.8); 0.4432 (1.0); 0.2549 (1.0); 0.2429 (3.7); 0.2312 (3.5); 0.2200 (0.8); 0.1453 (0.8); −0.0005 (145.3); −0.1501 (0.8) 512.8 I-68 [00212] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4917 (1.2); 9.4746 (1.2); 8.5463 (1.1); 8.5276 (1.1); 8.3197 (9.5); 8.2683 (5.8); 8.2231 (2.3); 8.1743 (2.4); 8.0960 (2.1); 6.0483 (0.9); 6.0310 (1.4); 6.0138 (0.9); 4.0758 (0.5); 4.0590 (0.8); 4.0408 (0.8); 4.0243 (0.5); 3.3360 (200.6); 3.3127 (5.3); 2.6763 (2.1); 2.6718 (2.9); 2.6674 (2.2); 2.5251 (9.4); 2.5117 (174.0); 2.5074 (344.9); 2.5029 (452.5); 2.4983 (338.2); 2.4940 (171.3); 2.3287 (16.0); 1.6115 (5.0); 1.5941 (5.0); 1.3736 (0.4); 1.1852 (12.6); 1.1687 (12.6); 0.1459 (2.0); 0.0080 (17.8); −0.0001 (458.2); −0.0083 (21.6); −0.1496 (2.1) 500.8 I-69 [00213] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5206 (1.3); 9.5026 (2.1); 9.4839 (1.2); 8.7520 (0.9); 8.7408 (0.9); 8.3186 (0.5); 8.2733 (2.2); 8.2377 (2.7); 8.2339 (2.9); 8.2104 (5.8); 8.1890 (3.1); 8.0974 (3.9); 6.0726 (1.0); 6.0553 (1.9); 6.0364 (1.8); 6.0189 (1.0); 5.7590 (0.9); 3.3347 (61.8); 2.8002 (5.4); 2.7888 (5.4); 2.6766 (1.2); 2.6722 (1.5); 2.6677 (1.1); 2.5257 (5.4); 2.5121 (94.9); 2.5077 (182.4); 2.5032 (233.6); 2.4987 (172.4); 2.4944 (85.6); 2.3325 (16.0); 2.3271 (14.6); 1.6181 (6.2); 1.6138 (5.9); 1.6007 (6.3); 1.5965 (5.7); 1.2334 (0.5); −0.0002 (0.9) 473.2 I-70 [00214] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4235 (1.5); 9.4066 (1.5); 8.3626 (6.0); 8.3601 (4.7); 8.3121 (2.5); 8.3087 (3.7); 8.3052 (2.0); 8.1275 (7.0); 6.0547 (1.0); 6.0375 (1.6); 6.0202 (1.0); 3.3277 (51.9); 3.2543 (1.4); 3.0264 (1.3); 2.6760 (0.4); 2.6717 (0.6); 2.6673 (0.4); 2.5072 (72.1); 2.5028 (92.2); 2.4983 (68.6); 2.3282 (16.0); 2.0753 (1.2); 1.6121 (5.7); 1.5947 (5.7); −0.0002 (1.2) 490.1 I-71 [00215] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3554 (1.5); 9.3382 (1.5); 8.1251 (6.5); 8.0679 (5.4); 8.0641 (8.9); 8.0553 (3.4); 8.0515 (3.1); 6.0305 (1.0); 6.0134 (1.6); 5.9960 (1.1); 3.3268 (108.8); 3.2551 (1.5); 3.0238 (1.4); 2.6755 (0.9); 2.6713 (1.2); 2.6668 (0.9); 2.5067 (147.7); 2.5023 (191.0); 2.4980 (146.7); 2.3263 (16.0); 1.5998 (5.8); 1.5824 (5.8); −0.0001 (1.8) 543.0 I-72 [00216] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3664 (1.3); 9.3492 (1.3); 8.3162 (0.7); 8.2489 (1.5); 8.0723 (5.1); 8.0681 (8.2); 8.0573 (2.8); 8.0532 (2.7); 8.0488 (1.2); 6.0387 (1.0); 6.0216 (1.5); 6.0043 (1.0); 4.6158 (1.6); 3.3251 (120.5); 2.6798 (0.9); 2.6755 (1.8); 2.6709 (2.4); 2.6665 (1.7); 2.5243 (8.0); 2.5108 (149.2); 2.5065 (293.2); 2.5020 (381.0); 2.4974 (279.8); 2.4931 (138.8); 2.3341 (16.0); 2.3246 (2.3); 1.6042 (5.2); 1.5867 (5.1); −0.0002 (2.6) 568.0 I-73 [00217] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5983 (1.5); 9.5812 (1.5); 9.2776 (2.5); 9.2734 (2.5); 9.1521 (2.3); 9.1493 (2.3); 8.6336 (2.3); 8.3167 (0.3); 8.2583 (1.6); 6.1148 (1.1); 6.0976 (1.7); 6.0803 (1.1); 4.6159 (1.8); 3.3258 (58.5); 2.6759 (0.8); 2.6713 (1.2); 2.6668 (0.9); 2.5246 (3.9); 2.5111 (72.0); 2.5068 (141.6); 2.5023 (184.4); 2.4978 (137.4); 2.4935 (69.7); 2.3418 (16.0); 2.3293 (1.6); 2.3250 (1.0); 2.0751 (1.5); 1.6410 (5.8); 1.6236 (5.8); −0.0001 (1.1) 479.2 I-74 [00218] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5792 (1.5); 9.5622 (1.5); 8.3394 (2.2); 8.3357 (3.7); 8.3320 (2.3); 8.3160 (0.5); 8.2878 (2.3); 8.2832 (3.3); 8.2792 (2.1); 8.2550 (1.7); 8.1445 (2.3); 8.1401 (3.3); 8.1358 (2.0); 6.0949 (1.0); 6.0777 (1.6); 6.0603 (1.0); 4.6149 (1.8); 3.3276 (148.7); 3.0446 (0.7); 3.0368 (0.8); 3.0251 (1.4); 3.0132 (0.8); 3.0053 (0.7); 2.9934 (0.4); 2.6757 (1.0); 2.6713 (1.3); 2.6667 (1.0); 2.5246 (4.3); 2.5112 (81.5); 2.5068 (158.8); 2.5023 (205.1); 2.4977 (150.3); 2.4933 (74.0); 2.3420 (16.0); 2.3293 (1.7); 2.3247 (1.1); 2.0748 (5.1); 1.6345 (5.6); 1.6171 (5.5); 1.2062 (1.1); 1.1965 (2.1); 1.1866 (2.0); 1.1185 (0.6); 1.1067 (1.8); 1.0991 (1.7); 1.0867 (1.8); 1.0817 (1.4); 1.0667 (0.3); −0.0002(1.4) 547.8 I-75 [00219] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4431 (1.5); 9.4263 (1.5); 8.3693 (6.0); 8.3657 (4.3); 8.3191 (2.9); 8.3157 (3.8); 8.3123 (2.1); 8.2545 (1.5); 6.0626 (1.1); 6.0454 (1.7); 6.0283 (1.1); 4.6164 (1.7); 3.3358 (130.6); 2.6763 (1.0); 2.6719 (1.4); 2.6675 (1.0); 2.5252 (4.7); 2.5073 (163.7); 2.5029 (214.8); 2.4984 (164.7); 2.3359 (16.0); 2.0764 (1.8); 1.6157 (5.6); 1.5983 (5.6); −0.0002 (0.8) 515.1 I-76 [00220] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3349 (1.4); 9.3179 (1.4); 8.3190 (0.5); 8.1937 (2.2); 8.1903 (3.7); 8.1869 (2.2); 8.1271 (6.7); 8.0404 (2.0); 8.0361 (3.0); 8.0321 (2.0); 7.9189 (2.2); 7.9148 (3.1); 7.9106 (2.0); 6.0254 (1.0); 6.0080 (1.6); 5.9908 (1.0); 3.3348 (154.0); 3.2943 (0.4); 3.2547 (1.5); 3.0255 (1.4); 2.6763 (1.2); 2.6718 (1.6); 2.6674 (1.2); 2.5250 (5.9); 2.5073 (189.7); 2.5028 (244.4); 2.4983 (183.3); 2.3254 (16.0); 1.5961 (5.5); 1.5786 (5.4); 0.1461 (0.8); 0.0077 (9.5); −0.0002 (193.5); −0.0084 (9.0); −0.1495 (0.9) 544.8 I-77 [00221] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.7406 (1.5); 9.7239 (1.5); 8.3191 (0.4); 8.2913 (3.7); 8.2335 (3.7); 8.1304 (6.4); 6.0908 (1.1); 6.0736 (1.7); 6.0564 (1.1); 3.6254 (0.4); 3.6151 (0.4); 3.3349 (145.3); 3.2529 (1.7); 3.1778 (0.4); 3.1584 (0.5); 3.1480 (0.6); 3.1402 (0.6); 3.1300 (0.5); 3.1115 (0.3); 3.0233 (1.7); 2.6895 (0.8); 2.6762 (1.3); 2.6718 (1.7); 2.6674 (1.3); 2.5073 (193.0); 2.5028 (245.8); 2.4984 (186.4); 2.3363 (16.0); 2.0762 (0.8); 1.6320 (5.8); 1.6146 (5.8); 1.2717 (2.5); 1.2573 (4.4); 1.2418 (3.8); 1.2234 (0.7); 0.1460 (0.9); 0.0077 (11.5); −0.0002 (189.7); −0.0083 (9.7); −0.1495 (0.8) 487.8 I-78 [00222] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5603 (1.5); 9.5432 (1.5); 8.3631 (3.6); 8.3187 (0.5); 8.2678 (3.2); 8.1720 (2.2); 8.1682 (3.3); 8.1353 (6.1); 6.0851 (1.0); 6.0679 (1.6); 6.0508 (1.0); 3.3848 (0.4); 3.3348 (193.6); 3.2561 (1.7); 3.1898 (0.3); 3.0246 (1.6); 2.6759 (1.6); 2.6718 (2.0); 2.5070 (257.9); 2.5028 (328.3); 2.4987 (254.1); 2.3327 (16.0); 1.6274 (5.7); 1.6099 (5.6); 0.1461 (1.1); −0.0002 (219.9); −0.0074 (13.3); −0.1494 (1.1) 496.8 I-79 [00223] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5713 (1.6); 9.5543 (1.6); 8.3670 (3.8); 8.2759 (2.5); 8.2718 (3.9); 8.2678 (3.0); 8.2608 (1.9); 8.1747 (2.3); 8.1705 (3.5); 8.1664 (2.1); 6.0934 (1.1); 6.0762 (1.8); 6.0589 (1.1); 4.6157 (1.9); 3.3344 (101.0); 2.6761 (0.9); 2.6718 (1.2); 2.6676 (0.9); 2.5072 (139.5); 2.5028 (179.9); 2.4985 (138.5); 2.3407 (16.0); 2.0867 (0.3); 2.0762 (1.0); 1.6321 (6.0); 1.6147 (6.0); 0.1459 (0.6); −0.0002 (129.8); −0.1496 (0.6) 521.8 I-80 [00224] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.7508 (1.5); 9.7339 (1.6); 8.3187 (0.5); 8.2960 (3.9); 8.2939 (4.0); 8.2532 (1.6); 8.2362 (4.1); 6.0979 (1.1); 6.0806 (1.7); 6.0634 (1.1); 4.6150 (1.7); 3.3377 (270.6); 2.6764 (1.2); 2.6720 (1.6); 2.6676 (1.2); 2.5252 (5.8); 2.5116 (99.0); 2.5075 (188.8); 2.5030 (245.4); 2.4986 (185.6); 2.3446 (16.0); 2.3348 (1.8); 2.3299 (1.8); 2.3255 (1.3); 2.0868 (4.4); 2.0761 (0.9); 1.6365 (5.9); 1.6191 (5.9); 0.1460 (0.7); 0.0078 (7.3); −0.0002 (158.4); −0.0083 (7.4); −0.1496 (0.7) 512.8 I-81 [00225] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3475 (1.5); 9.3305 (1.6); 8.2522 (1.6); 8.2007 (2.3); 8.1973 (3.8); 8.1939 (2.3); 8.0424 (2.1); 8.0382 (3.2); 8.0342 (2.1); 7.9239 (2.3); 7.9199 (3.3); 7.9157 (2.1); 6.0351 (1.1); 6.0178 (1.6); 6.0005 (1.1); 4.6162 (1.7); 3.3353 (98.9); 2.6764 (0.7); 2.6720 (1.0); 2.6677 (0.7); 2.5074 (114.8); 2.5030 (148.0); 2.4985 (110.8); 2.3336 (16.0); 2.0763 (0.6); 1.6009 (5.7); 1.5835 (5.6); 0.1460 (0.5); 0.0078 (5.0); −0.0002 (107.1); −0.0084 (4.8); −0.1495 (0.5) 569.7 I-82 [00226] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.7395 (2.5); 9.7231 (2.5); 8.6789 (16.0); 8.6739 (5.4); 8.5452 (4.4); 8.4265 (4.5); 8.3379 (10.9); 6.1245 (0.4); 6.1072 (1.7); 6.0902 (2.6); 6.0732 (1.7); 6.0557 (0.4); 3.4074 (0.7); 3.3895 (27.1); 3.3339 (87.1); 2.6770 (0.6); 2.6726 (0.6); 2.6681 (0.5); 2.5260 (2.2); 2.5125 (40.3); 2.5081 (78.6); 2.5036 (101.4); 2.4990 (73.9); 2.4946 (35.6); 2.3349 (0.4); 2.3304 (0.6); 2.3259 (0.4); 2.0763 (3.4); 1.6630 (10.0); 1.6455 (10.0); 0.0080 (2.5); −0.0002 (62.9); −0.0085 (2.1) 471.1 I-83 [00227] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.7127 (1.4); 9.6956 (1.4); 8.6977 (2.7); 8.5697 (2.4); 8.4211 (2.4); 8.1376 (7.2); 6.1263 (1.0); 6.1091 (1.6); 6.0918 (1.0); 3.3908 (15.0); 3.3332 (105.7); 3.2487 (1.3); 3.0232 (1.3); 2.6764 (0.6); 2.6718 (0.8); 2.6674 (0.6); 2.5254 (2.5); 2.5118 (47.6); 2.5074 (95.2); 2.5029 (125.2); 2.4983 (93.1); 2.4939 (46.2); 2.3353 (16.0); 1.6487 (5.3); 1.6312 (5.3); 0.1459 (0.4); 0.0080 (3.3); −0.0001 (90.0); −0.0085 (3.6); −0.1495 (0.4) 530.8 I-84 [00228] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.7231 (1.5); 9.7060 (1.6); 8.7014 (2.9); 8.5735 (2.6); 8.4231 (2.7); 8.2624 (1.6); 6.1350 (1.0); 6.1177 (1.6); 6.1005 (1.1); 4.6152 (1.7); 3.3917 (16.2); 3.3323 (101.2); 2.6762 (0.6); 2.6718 (0.8); 2.6675 (0.6); 2.5252 (2.5); 2.5117 (50.3); 2.5073 (99.0); 2.5028 (129.4); 2.4983 (96.0); 2.4939 (47.7); 2.3433 (16.0); 2.3299 (1.2); 2.3253 (0.8); 2.0758 (4.4); 1.6534 (5.5); 1.6360 (5.5); 0.1459 (0.4); 0.0080 (3.4); −0.0002 (89.2); −0.0085 (3.6); −0.1496 (0.4) 555.8 I-85 [00229] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5451 (1.7); 9.5287 (1.7); 8.6703 (7.9); 8.3241 (6.9); 8.1769 (3.3); 8.1729 (2.3); 8.1366 (3.2); 8.0401 (3.0); 6.0566 (1.2); 6.0396 (1.8); 6.0226 (1.2); 3.3254 (40.1); 2.6726 (0.4); 2.5257 (1.4); 2.5124 (24.7); 2.5080 (47.3); 2.5035 (60.2); 2.4990 (43.1); 2.4947 (20.9); 2.3301 (0.4); 2.0120 (0.4); 1.9896 (0.6); 1.6394 (7.1); 1.6219 (7.1); 1.3977 (16.0); 1.1759 (0.4); 0.8889 (0.5); 0.8722 (0.4); 0.1460 (0.4); 0.0079 (4.0); −0.0002 (84.6); −0.0076 (3.5); −0.0149 (0.5); −0.1494 (0.4) 443.0 I-86 [00230] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5432 (1.0); 9.5268 (1.0); 8.6704 (5.4); 8.3232 (4.4); 8.1476 (2.0); 8.1435 (1.3); 8.0966 (1.9); 7.9889 (1.9); 6.0552 (0.7); 6.0381 (1.1); 6.0210 (0.7); 3.3235 (39.6); 2.6762 (0.3); 2.6715 (0.4); 2.6670 (0.3); 2.5247 (1.5); 2.5115 (28.2); 2.5071 (54.5); 2.5026 (69.5); 2.4980 (49.3); 2.4936 (23.5); 2.3293 (0.4); 1.9890 (0.6); 1.6384 (4.3); 1.6209 (4.2); 1.3978 (16.0); 1.2349 (1.3); 1.1755 (0.3); 0.1461 (0.4); 0.0079 (4.8); −0.0002 (97.5); −0.0085 (3.9); −0.1496 (0.4) 488.9 I-87 [00231] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4374 (3.0); 9.4210 (3.1); 8.6695 (16.0); 8.3223 (13.1); 8.3138 (0.6); 7.8494 (3.9); 7.8457 (6.7); 7.8419 (4.3); 7.7625 (4.4); 7.7601 (4.0); 7.4941 (4.5); 6.0738 (0.5); 6.0568 (2.1); 6.0398 (3.2); 6.0228 (2.1); 6.0055 (0.4); 5.7567 (9.1); 3.3296 (27.6); 2.5276 (1.0); 2.5144 (18.0); 2.5100 (36.0); 2.5054 (46.8); 2.5009 (33.3); 2.4964 (16.0); 1.8630 (2.4); 1.8506 (6.6); 1.8432 (7.1); 1.8317 (3.0); 1.7920 (0.4); 1.7106 (0.4); 1.6716 (3.6); 1.6593 (7.3); 1.6519 (7.7); 1.6435 (13.0); 1.6260 (12.4); 0.0079 (1.3); −0.0002 (33.7); −0.0085 (1.2) 474.1 I-88 [00232] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.2713 (3.6); 9.2549 (3.7); 8.6668 (16.0); 8.3081 (14.2); 7.7288 (8.0); 7.7256 (5.3); 7.5318 (7.4); 7.5275 (10.5); 7.5229 (7.3); 7.5172 (2.6); 6.0407 (0.5); 6.0239 (2.3); 6.0069 (3.6); 5.9899 (2.3); 5.9727 (0.5); 4.9052 (2.2); 4.8832 (6.9); 4.8612 (7.3); 4.8391 (2.5); 3.3244 (90.7); 2.6760 (0.9); 2.6716 (1.2); 2.6672 (0.9); 2.5245 (4.1); 2.5070 (145.4); 2.5026 (188.6); 2.4982 (138.5); 2.3336 (0.8); 2.3294 (1.2); 2.3250 (0.9); 1.6153 (13.8); 1.5978 (13.8); 0.0076 (1.2); 0.0000 (30.5); −0.0081 (1.4) 501.0/ 503.0 I-89 [00233] .sup.1H-NMR(600.1 MHz, CD3CN lowT): δ = 8.0126 (5.8); 7.9164 (8.6); 7.9056 (1.3); 7.4650 (2.5); 7.4366 (3.7); 7.1974 (2.5); 6.1364 (1.1); 6.1247 (1.8); 6.1128 (1.2); 5.4725 (2.0); 3.2618 (16.0); 3.0503 (14.8); 2.2936 (15.3); 2.0724 (0.4); 2.0216 (0.3); 2.0133 (0.7); 2.0075 (0.8); 1.9993 (1.4); 1.9911 (0.9); 1.9855 (0.9); 1.9775 (1.2); 1.9697 (22.0); 1.9656 (42.8); 1.9615 (62.4); 1.9574 (43.6); 1.9533 (22.3); 1.8464 (0.4); 1.6534 (7.0); 1.6417 (7.0); 1.0739 (0.6); 1.0664 (2.4); 1.0630 (2.6); 1.0524 (2.4); 1.0491 (2.4); 1.0424 (0.7); 0.7971 (0.9); 0.7897 (2.7); 0.7867 (2.4); 0.7816 (2.6); 0.7789 (2.6); 0.7711 (0.8); 0.0054 (2.1); −0.0001 (58.1); −0.0056 (2.2) 495.1 I-90 [00234] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6669 (1.5); 9.6503 (1.6); 8.6370 (7.6); 8.5303 (5.7); 8.3446 (2.5); 8.3157 (0.5); 6.0790 (1.1); 6.0619 (1.6); 6.0446 (1.1); 3.3234 (135.3); 2.6754 (1.4); 2.6709 (1.9); 2.6665 (1.4); 2.5239 (6.8); 2.5064 (237.6); 2.5020 (302.9); 2.4976 (221.7); 2.3478 (16.0); 2.3332 (1.6); 2.3288 (2.0); 2.3244 (1.5); 2.0745 (1.4); 1.6367 (6.0); 1.6192 (5.9); 0.0080 (1.5); −0.0002 (37.3); −0.0083 (1.7) 475.1 I-91 [00235] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.2593 (1.6); 9.2426 (1.6); 8.6318 (7.0); 7.5763 (3.2); 7.5569 (2.2); 7.2980 (2.2); 6.0119 (1.1); 5.9947 (1.6); 5.9775 (1.1); 3.3243 (53.6); 2.6755 (0.5); 2.6712 (0.7); 2.6666 (0.5); 2.5241 (2.6); 2.5105 (48.1); 2.5066 (90.4); 2.5022 (113.9); 2.4977 (81.2); 2.4935 (39.6); 2.3404 (16.0); 2.3294 (1.1); 2.3247 (0.7); 2.0749 (1.0); 2.0666 (0.7); 2.0544 (1.3); 2.0420 (0.8); 2.0336 (0.7); 2.0209 (0.3); 1.6047 (6.0); 1.5872 (6.0); 1.0580 (0.6); 1.0470 (2.2); 1.0414 (2.4); 1.0313 (1.1); 1.0260 (2.2); 1.0207 (2.3); 1.0106 (0.8); 0.8125 (0.9); 0.8020 (2.4); 0.7971 (2.3); 0.7899 (2.4); 0.7848 (2.3); 0.7736 (0.7); −0.0002 (13.8); −0.0085 (0.5) 463.1 I-92 [00236] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4322 (1.0); 9.4155 (1.0); 8.6350 (4.6); 8.0503 (2.0); 8.0467 (1.4); 7.8475 (1.5); 7.6952 (1.5); 6.0462 (0.7); 6.0291 (1.0); 6.0120 (0.7); 3.3284 (17.0); 2.5265 (0.6); 2.5088 (20.6); 2.5043 (26.6); 2.4998 (19.6); 2.3492 (10.1); 1.7419 (16.0); 1.6306 (3.7); 1.6132 (3.7); −0.0002 (1.4) 517.0 I-93 [00237] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6552 (2.8); 9.6388 (2.8); 8.6728 (16.0); 8.4724 (3.9); 8.4688 (7.0); 8.4652 (4.1); 8.3330 (12.2); 8.1516 (4.0); 8.1494 (3.8); 8.1027 (4.0); 6.1022 (0.4); 6.0850 (1.8); 6.0679 (2.8); 6.0508 (1.9); 6.0335 (0.4); 3.3644 (31.9); 3.3282 (105.6); 2.6767 (0.5); 2.6723 (0.7); 2.6677 (0.5); 2.5258 (2.3); 2.5210 (3.7); 2.5124 (42.6); 2.5079 (86.0); 2.5034 (111.5); 2.4988 (79.6); 2.4943 (38.5); 2.3347 (0.5); 2.3302 (0.7); 2.3256 (0.5); 2.0754 (0.4); 1.6540 (11.2); 1.6366 (11.2); −0.0002 (1.8) 487.1 I-94 [00238] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3442 (2.9); 9.3278 (2.9); 8.6666 (16.0); 8.3140 (12.5); 7.5544 (11.8); 7.5489 (12.2); 7.5250 (6.6); 7.3417 (13.9); 7.2494 (3.1); 7.2440 (5.5); 7.2386 (2.9); 7.1583 (6.8); 6.0561 (0.4); 6.0392 (2.0); 6.0222 (3.0); 6.0051 (2.0); 5.9877 (0.4); 3.3266 (149.4); 2.6761 (0.8); 2.6715 (1.1); 2.6670 (0.8); 2.5250 (3.4); 2.5202 (5.6); 2.5115 (64.6); 2.5071 (130.5); 2.5025 (170.1); 2.4980 (121.9); 2.4935 (58.7); 2.3339 (0.8); 2.3293 (1.1); 2.3248 (0.8); 2.0746 (1.5); 1.6284 (11.9); 1.6110 (11.9); 0.0080 (1.1); −0.0002 (30.1); −0.0085 (1.0) 457.1 I-95 [00239] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.2654 (3.1); 9.2490 (3.1); 8.6731 (14.8); 8.3171 (1.4); 8.3077 (12.1); 8.1821 (0.4); 8.0266 (0.5); 7.9435 (0.4); 7.7817 (5.3); 7.5994 (5.4); 7.4497 (5.3); 6.0633 (0.5); 6.0463 (2.2); 6.0292 (3.3); 6.0121 (2.2); 5.9944 (0.5); 3.3261 (89.0); 2.6760 (0.7); 2.6716 (1.0); 2.6672 (0.7); 2.5246 (4.1); 2.5113 (63.1); 2.5071 (120.5); 2.5027 (153.4); 2.4982 (110.2); 2.4940 (54.3); 2.3339 (0.7); 2.3295 (1.0); 2.3250 (0.7); 2.0862 (0.7); 2.0748 (4.5); 2.0652 (1.5); 2.0528 (3.2); 2.0402 (1.6); 2.0317 (1.6); 2.0198 (7.8); 2.0058 (1.6); 1.9727 (16.0); 1.9582 (1.0); 1.9254 (8.1); 1.6302 (13.1); 1.6127 (13.0); 1.0380 (1.3); 1.0271 (4.4); 1.0217 (4.8); 1.0114 (2.1); 1.0061 (4.5); 1.0008 (4.6); 0.9908 (1.5); 0.7955 (1.8); 0.7852 (4.7); 0.7806 (4.7); 0.7729 (4.7); 0.7683 (4.6); 0.7570 (1.5); 0.0079 (0.5); −0.0002 (11.6); −0.0085 (0.5) 429.2 I-96 [00240] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4506 (3.6); 9.4343 (3.7); 8.6670 (16.0); 8.3202 (14.2); 8.0185 (4.8); 8.0147 (7.8); 8.0109 (5.1); 7.8021 (5.6); 7.7903 (6.0); 6.0542 (0.5); 6.0369 (2.4); 6.0200 (3.8); 6.0030 (2.5); 5.9857 (0.6); 3.3300 (55.8); 2.6784 (0.4); 2.6740 (0.5); 2.6696 (0.4); 2.5273 (1.5); 2.5094 (59.5); 2.5050 (76.3); 2.5005 (54.9); 2.3364 (0.3); 2.3317 (0.5); 2.3273 (0.3); 2.0769 (0.4); 1.6297 (14.9); 1.6122 (14.8); −0.0002 (5.9) 443.1 I-97 [00241] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5455 (3.4); 9.5291 (3.4); 8.6715 (16.0); 8.3166 (14.2); 8.2437 (11.6); 7.9544 (5.2); 7.3280 (5.1); 7.1894 (11.4); 7.0508 (5.4); 6.0841 (0.5); 6.0668 (2.4); 6.0498 (3.7); 6.0327 (2.4); 6.0155 (0.5); 3.3266 (58.6); 2.6768 (0.6); 2.6722 (0.8); 2.6677 (0.6); 2.5255 (2.9); 2.5120 (51.5); 2.5077 (101.2); 2.5033 (130.1); 2.4987 (92.9); 2.4944 (44.9); 2.3346 (0.6); 2.3300 (0.8); 2.3256 (0.6); 2.0752 (4.7); 1.6417 (14.6); 1.6243 (14.6); 0.0078 (0.4); −0.0002 (10.2); −0.0085 (0.4) 425.1 I-98 [00242] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5335 (3.2); 9.5173 (3.2); 8.6696 (16.0); 8.3216 (13.3); 8.1540 (5.6); 7.9972 (4.4); 7.7986 (4.3); 7.3015 (2.5); 7.1633 (5.6); 7.0251 (2.7); 6.0779 (0.5); 6.0605 (2.2); 6.0436 (3.3); 6.0265 (2.2); 6.0092 (0.5); 3.3314 (46.8); 2.6743 (0.4); 2.5276 (1.3); 2.5141 (24.0); 2.5098 (47.6); 2.5053 (61.8); 2.5008 (44.6); 2.4964 (21.8); 2.3321 (0.4); 2.0771 (1.0); 1.6426 (13.2); 1.6252 (13.1); −0.0002 (4.8) 459.1 I-99 [00243] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3434 (1.7); 9.3269 (1.7); 8.6715 (8.1); 8.3129 (6.9); 8.0005 (2.1); 7.9966 (3.6); 7.9927 (2.3); 7.8696 (3.5); 7.7614 (3.3); 6.0373 (1.1); 6.0202 (1.7); 6.0031 (1.1); 3.3253 (47.7); 2.6762 (0.4); 2.6716 (0.5); 2.6671 (0.4); 2.5245 (1.8); 2.5112 (32.8); 2.5071 (63.4); 2.5027 (81.5); 2.4982 (59.0); 2.4938 (29.3); 2.3339 (0.4); 2.3294 (0.5); 2.3251 (0.4); 2.0750 (5.5); 1.6914 (15.6); 1.6355 (16.0); 1.6261 (7.3); 1.6086 (6.8); −0.0002 (6.1) 465.1 I-100 [00244] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4382 (3.6); 9.4218 (3.6); 8.6676 (16.0); 8.3201 (14.2); 7.7344 (5.9); 7.7317 (6.0); 7.7282 (7.4); 7.7226 (6.3); 7.5658 (3.7); 7.4859 (5.1); 7.3830 (7.7); 7.2001 (3.9); 6.0615 (0.5); 6.0441 (2.4); 6.0272 (3.6); 6.0102 (2.4); 5.9927 (0.5); 3.3320 (168.5); 2.6766 (1.2); 2.6722 (1.5); 2.6677 (1.1); 2.5254 (5.7); 2.5119 (95.3); 2.5077 (180.7); 2.5032 (228.9); 2.4987 (166.1); 2.4944 (81.7); 2.3345 (1.1); 2.3301 (1.5); 2.3257 (1.1); 1.6338 (14.4); 1.6164 (14.3); 0.1461 (0.9); 0.0079 (8.7); −0.0001 (194.7); −0.0084 (7.8); −0.1495 (0.9) 475.1 I-101 [00245] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4576 (4.2); 9.4412 (4.2); 8.6686 (14.6); 8.3230 (13.4); 8.2647 (15.9); 8.2618 (14.4); 8.2121 (6.5); 8.2080 (8.4); 8.2039 (5.0); 6.0572 (0.7); 6.0405 (2.8); 6.0235 (4.2); 6.0065 (2.8); 5.9894 (0.7); 3.3341 (55.8); 2.6737 (0.7); 2.5089 (80.7); 2.5047 (97.3); 2.5005 (74.7); 2.3354 (0.5); 2.3316 (0.6); 2.0771 (4.6); 1.6281 (16.0); 1.6107 (15.8); 1.1243 (0.3); −0.0002 (55.3) 384.0 I-102 [00246] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6499 (1.3); 9.6329 (1.4); 8.7557 (0.4); 8.7460 (1.0); 8.7344 (1.1); 8.7243 (0.4); 8.5268 (4.6); 8.3386 (2.0); 8.3158 (0.4); 8.2114 (6.9); 6.0948 (1.0); 6.0776 (1.5); 6.0603 (1.0); 3.3560 (16.0); 2.7998 (6.5); 2.7883 (6.4); 2.6903 (0.6); 2.6807 (0.4); 2.6763 (0.8); 2.6718 (1.0); 2.6673 (0.8); 2.6626 (0.4); 2.5253 (3.2); 2.5205 (5.0); 2.5118 (63.2); 2.5074 (129.3); 2.5029 (169.0); 2.4983 (119.2); 2.4937 (56.0); 2.3294 (16.0); 1.6350 (5.2); 1.6175 (5.2); 0.9759 (0.4); 0.1459 (0.7); 0.0080 (5.7); −0.0001 (162.0); −0.0085 (5.6); −0.1495 (0.7) 507.2 I-103 [00247] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6730 (2.7); 9.6563 (2.7); 8.6614 (4.9); 8.6194 (16.0); 8.5852 (0.4); 8.5274 (4.3); 8.4206 (4.4); 8.3159 (0.4); 6.0682 (0.4); 6.0509 (1.9); 6.0338 (2.9); 6.0167 (1.9); 5.9995 (0.4); 3.3882 (29.6); 3.3253 (145.0); 2.6808 (0.4); 2.6762 (0.9); 2.6716 (1.2); 2.6670 (0.9); 2.6624 (0.4); 2.5251 (4.0); 2.5204 (6.0); 2.5117 (72.8); 2.5072 (149.9); 2.5027 (196.1); 2.4981 (136.9); 2.4936 (63.1); 2.3386 (0.4); 2.3340 (0.9); 2.3295 (1.2); 2.3249 (0.8); 2.3204 (0.4); 2.1157 (0.5); 2.1036 (1.2); 2.0949 (1.3); 2.0830 (2.5); 2.0709 (1.4); 2.0622 (1.3); 2.0500 (0.6); 1.6226 (9.9); 1.6051 (9.8); 1.0554 (0.6); 1.0380 (3.7); 1.0348 (4.0); 1.0175 (3.6); 1.0140 (3.6); 0.9989 (0.6); 0.9858 (0.3); 0.9163 (0.4); 0.9133 (0.4); 0.9050 (0.5); 0.9006 (0.6); 0.8949 (1.4); 0.8877 (1.8); 0.8828 (2.7); 0.8769 (3.0); 0.8720 (2.6); 0.8683 (2.3); 0.8605 (1.2); 0.8495 (0.4); 0.8452 (0.5); 0.1458 (1.6); 0.0079 (14.4); −0.0002 (377.0); −0.0086 (12.2); −0.1497 (1.6) 511.0 I-104 [00248] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6160 (2.2); 9.5993 (2.3); 8.6166 (16.0); 8.6105 (0.7); 8.4178 (3.2); 8.4141 (5.9); 8.4105 (3.2); 8.3159 (0.4); 8.1425 (3.1); 8.1400 (2.9); 8.0732 (3.2); 6.0425 (0.3); 6.0252 (1.6); 6.0082 (2.5); 5.9911 (1.6); 5.9741 (0.3); 3.3251 (55.2); 3.0710 (0.5); 3.0591 (1.1); 3.0514 (1.1); 3.0468 (0.7); 3.0397 (2.2); 3.0315 (0.8); 3.0276 (1.2); 3.0199 (1.1); 3.0080 (0.5); 2.6809 (0.4); 2.6764 (0.7); 2.6718 (1.0); 2.6672 (0.7); 2.6627 (0.4); 2.5253 (3.2); 2.5206 (4.7); 2.5119 (61.0); 2.5074 (126.3); 2.5028 (164.8); 2.4982 (113.8); 2.4936 (51.6); 2.3342 (0.7); 2.3296 (1.0); 2.3251 (0.7); 2.1168 (0.5); 2.1047 (1.0); 2.0960 (1.1); 2.0929 (0.9); 2.0840 (2.2); 2.0749 (1.5); 2.0719 (1.2); 2.0632 (1.1); 2.0510 (0.6); 1.6141 (8.6); 1.5966 (8.6); 1.5852 (0.6); 1.5668 (0.4); 1.2503 (0.3); 1.2380 (0.4); 1.2273 (1.5); 1.2137 (2.5); 1.2057 (2.9); 1.1946 (1.9); 1.1840 (0.6); 1.1717 (0.5); 1.1585 (0.5); 1.1448 (0.5); 1.1359 (0.8); 1.1218 (3.0); 1.1162 (2.4); 1.1022 (2.9); 1.0968 (1.9); 1.0942 (2.1); 1.0798 (0.4); 553.0 1.0707 (0.3); 1.0580 (0.4); 1.0400 (3.0); 1.0362 (3.6); 1.0194 (3.2); 1.0152 (3.4); 0.9989 (0.5); 0.9143 (0.4); 0.9065 (0.4); 0.9016 (0.5); 0.8939 (1.3); 0.8901 (1.5); 0.8845 (1.5); 0.8815 (1.8); 0.8780 (2.5); 0.8728 (2.1); 0.8675 (1.7); 0.8577 (1.2); 0.8470 (0.4); 0.8430 (0.5); 0.1459 (1.4); 0.0186 (0.4); 0.0138 (1.0); 0.0079 (11.8); −0.0001 (337.1); −0.0086 (10.5); −0.0176 (0.5); −0.0222 (0.4); −0.1496 (1.4) I-105 [00249] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4368 (3.1); 9.4203 (3.2); 8.7952 (0.9); 8.7849 (2.4); 8.7734 (2.4); 8.7625 (0.8); 8.2527 (14.8); 8.2433 (16.0); 8.0149 (4.3); 8.0109 (7.0); 8.0069 (4.7); 7.8035 (4.8); 7.7859 (4.8); 7.7835 (4.8); 6.0679 (0.5); 6.0509 (2.2); 6.0338 (3.3); 6.0167 (2.2); 5.9994 (0.5); 3.3514 (214.2); 2.8101 (15.7); 2.7986 (15.4); 2.7164 (0.5); 2.6809 (0.3); 2.6763 (0.4); 2.6718 (0.3); 2.5466 (137.1); 2.5295 (1.6); 2.5161 (28.0); 2.5118 (56.7); 2.5073 (74.6); 2.5027 (53.2); 2.4983 (25.3); 2.3729 (0.5); 2.3385 (0.3); 2.3340 (0.4); 1.6295 (12.8); 1.6121 (12.7) 475.3 I-106 [00250] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4508 (2.4); 9.4341 (2.5); 8.2527 (12.5); 8.1600 (16.0); 8.0241 (3.8); 8.0200 (6.1); 8.0160 (3.9); 7.8011 (6.8); 7.7990 (7.1); 6.0858 (0.4); 6.0685 (1.7); 6.0514 (2.7); 6.0342 (1.8); 6.0169 (0.4); 3.3591 (74.9); 3.2564 (2.2); 3.0306 (2.1); 2.7164 (0.6); 2.5653 (0.4); 2.5465 (169.5); 2.5295 (0.9); 2.5248 (1.2); 2.5161 (17.2); 2.5116 (35.9); 2.5071 (47.2); 2.5025 (32.9); 2.4979 (15.0); 2.3727 (0.6); 1.6392 (10.4); 1.6217 (10.3) 489.3 I-107 [00251] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.2696 (1.8); 9.2530 (1.9); 8.7980 (0.5); 8.7872 (1.5); 8.7757 (1.5); 8.7650 (0.5); 8.2453 (16.0); 7.5495 (4.2); 7.5458 (3.4); 7.5395 (2.6); 7.5368 (2.8); 7.2969 (2.7); 6.0459 (1.3); 6.0288 (1.9); 6.0116 (1.3); 3.3502 (127.0); 2.8115 (9.4); 2.8000 (9.2); 2.7163 (0.4); 2.5614 (0.5); 2.5468 (130.9); 2.5298 (0.8); 2.5250 (1.2); 2.5163 (17.6); 2.5119 (36.5); 2.5073 (47.8); 2.5028 (33.7); 2.4982 (15.8); 2.3725 (0.4); 2.0851 (0.4); 2.0726 (0.8); 2.0642 (0.9); 2.0606 (0.6); 2.0518 (1.7); 2.0394 (0.9); 2.0309 (0.9); 2.0183 (0.4); 1.6276 (7.4); 1.6101 (7.4); 1.0572 (1.0); 1.0460 (2.8); 1.0405 (3.0); 1.0366 (1.6); 1.0299 (1.6); 1.0251 (2.8); 1.0195 (2.8); 1.0092 (1.2); 0.8108 (1.2); 0.8001 (3.2); 0.7950 (3.1); 0.7878 (3.0); 0.7827 (3.4); 0.7712 (1.0) 481.3 I-108 [00252] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6739 (2.7); 9.6572 (2.8); 8.7950 (0.7); 8.7840 (2.1); 8.7725 (2.1); 8.7619 (0.7); 8.5091 (9.6); 8.4384 (0.3); 8.3482 (4.3); 8.2662 (13.9); 8.2484 (16.0); 6.1274 (0.4); 6.1106 (1.9); 6.0936 (2.9); 6.0764 (1.9); 6.0591 (0.4); 3.3457 (473.8); 2.8094 (14.2); 2.7979 (14.1); 2.6851 (0.4); 2.6807 (0.9); 2.6761 (1.2); 2.6715 (0.9); 2.6671 (0.4); 2.5465 (28.8); 2.5296 (3.2); 2.5249 (4.9); 2.5162 (73.6); 2.5117 (153.8); 2.5072 (203.4); 2.5025 (142.0); 2.4980 (64.8); 2.3430 (0.4); 2.3385 (0.8); 2.3339 (1.2); 2.3294 (0.8); 2.3249 (0.4); 2.0791 (0.6); 1.6606 (11.2); 1.6432 (11.2); 0.0032 (0.4) 493.3 I-109 [00253] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3597 (1.8); 9.3430 (1.8); 8.7984 (0.5); 8.7880 (1.4); 8.7762 (1.4); 8.7651 (0.4); 8.2463 (16.0); 7.9696 (2.7); 7.9658 (4.5); 7.9619 (2.7); 7.6582 (1.7); 7.6529 (3.5); 7.6484 (2.6); 7.6356 (2.6); 7.6322 (2.9); 7.5290 (2.2); 7.3457 (4.8); 7.1624 (2.3); 6.0433 (1.2); 6.0262 (1.9); 6.0091 (1.2); 3.3789 (0.4); 3.3514 (189.4); 3.3345 (1.2); 2.8115 (9.2); 2.8001 (9.0); 2.7164 (0.8); 2.6761 (0.3); 2.5661 (0.4); 2.5599 (1.1); 2.5467 (217.9); 2.5296 (1.2); 2.5249 (1.4); 2.5163 (19.2); 2.5117 (40.4); 2.5072 (53.3); 2.5025 (37.1); 2.4980 (16.9); 2.3729 (0.8); 2.3339 (0.3); 1.6221 (7.2); 1.6046 (7.2) 503.2 I-110 [00254] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.7344 (2.8); 9.7177 (2.9); 8.7922 (0.7); 8.7820 (2.2); 8.7705 (2.2); 8.7591 (0.8); 8.5554 (3.8); 8.5512 (6.3); 8.5469 (4.8); 8.5036 (5.7); 8.4354 (3.2); 8.4314 (5.2); 8.2697 (14.2); 8.2411 (16.0); 6.1143 (0.4); 6.0972 (2.0); 6.0802 (3.0); 6.0631 (2.0); 6.0459 (0.4); 3.3492 (264.6); 2.8089 (15.0); 2.7974 (14.8); 2.7160 (0.9); 2.6808 (0.4); 2.6762 (0.6); 2.6716 (0.4); 2.5696 (0.4); 2.5638 (0.5); 2.5593 (1.0); 2.5466 (259.0); 2.5297 (1.7); 2.5250 (2.2); 2.5163 (35.2); 2.5118 (75.1); 2.5072 (100.7); 2.5026 (70.8); 2.4980 (32.7); 2.3724 (0.8); 2.3386 (0.4); 2.3340 (0.6); 2.3294 (0.4); 1.9133 (0.6); 1.6529 (11.7); 1.6355 (11-6) 523.2 I-111 [00255] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4374 (2.6); 9.4208 (2.7); 8.7955 (0.7); 8.7852 (2.0); 8.7736 (2.0); 8.7628 (0.6); 8.2527 (13.6); 8.2434 (16.0); 8.1475 (3.8); 8.1436 (6.5); 8.1398 (4.1); 7.9093 (3.8); 7.8126 (3.6); 7.8099 (4.0); 7.8073 (3.4); 6.0664 (0.4); 6.0491 (1.8); 6.0320 (2.8); 6.0149 (1.8); 5.9976 (0.4); 3.3488 (169.4); 2.8104 (13.7); 2.7989 (13.5); 2.7165 (1.4); 2.6807 (0.4); 2.6762 (0.5); 2.6715 (0.4); 2.5710 (0.6); 2.5659 (1.1); 2.5600 (1.6); 2.5467 (377.4); 2.5300 (1.6); 2.5248 (1.9); 2.5163 (28.9); 2.5117 (61.6); 2.5072 (82.4); 2.5025 (58.1); 2.4980 (26.8); 2.3725 (1.4); 2.3385 (0.4); 2.3339 (0.5); 2.3294 (0.4); 1.6276 (10.7); 1.6102 (10.6) 521.1 I-112 [00256] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3345 (1.9); 9.3179 (1.9); 8.7989 (0.5); 8.7883 (1.5); 8.7767 (1.5); 8.7664 (0.5); 8.2486 (16.0); 7.5594 (8.5); 7.5539 (8.7); 7.5268 (4.9); 7.3435 (10.5); 7.2517 (2.2); 7.2463 (3.9); 7.2408 (2.0); 7.1601 (5.2); 6.0600 (1.4); 6.0429 (2.1); 6.0257 (1.4); 3.3500 (124.3); 2.8123 (10.6); 2.8008 (10.3); 2.7165 (1.0); 2.5719 (0.4); 2.5618 (1.1); 2.5468 (261.5); 2.5336 (1.1); 2.5295 (0.8); 2.5248 (1.2); 2.5162 (15.3); 2.5117 (32.2); 2.5071 (43.0); 2.5025 (30.2); 2.4979 (14.0); 2.3729 (1.0); 1.6313 (8.1); 1.6138 (8.0) 489.3 I-113 [00257] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6431 (2.8); 9.6265 (2.9); 8.7971 (0.7); 8.7861 (2.2); 8.7746 (2.2); 8.7633 (0.7); 8.4763 (4.0); 8.4727 (7.3); 8.4690 (4.1); 8.2666 (14.6); 8.2506 (16.0); 8.2455 (1.0); 8.1496 (3.9); 8.1473 (3.7); 8.1029 (4.0); 6.1208 (0.4); 6.1037 (1.9); 6.0865 (2.9); 6.0694 (1.9); 6.0517 (0.4); 3.3887 (0.3); 3.3671 (35.2); 3.3464 (228.0); 2.8104 (14.5); 2.7989 (14.2); 2.7164 (0.8); 2.6806 (0.4); 2.6761 (0.5); 2.6716 (0.3); 2.5596 (1.1); 2.5589 (1.1); 2.5466 (236.5); 2.5351 (0.4); 2.5295 (1.2); 2.5249 (1.8); 2.5162 (27.8); 2.5117 (58.8); 2.5071 (77.7); 2.5025 (53.9); 2.4979 (24.4); 2.4831 (0.4); 2.3728 (0.8); 2.3386 (0.3); 2.3339 (0.5); 1.6557 (11.0); 1.6383 (11.0); 1.6167 (0.4) 519.3 I-114 [00258] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6883 (2.5); 9.6718 (2.6); 8.7954 (0.6); 8.7848 (2.0); 8.7732 (2.0); 8.7625 (0.6); 8.4747 (3.8); 8.4704 (5.8); 8.4661 (4.2); 8.3904 (3.6); 8.3866 (6.6); 8.3828 (3.6); 8.2655 (13.4); 8.2467 (16.0); 8.2061 (3.6); 8.2017 (6.0); 8.1973 (3.3); 7.5535 (2.2); 7.4235 (5.3); 7.2937 (2.7); 6.1082 (0.4); 6.0910 (1.8); 6.0740 (2.7); 6.0569 (1.8); 6.0394 (0.4); 3.3430 (176.5); 2.8107 (13.8); 2.7992 (13.6); 2.7160 (0.8); 2.6806 (0.4); 2.6761 (0.5); 2.6715 (0.4); 2.5637 (0.7); 2.5604 (1.0); 2.5465 (262.3); 2.5298 (1.2); 2.5249 (2.0); 2.5162 (30.8); 2.5117 (65.7); 2.5071 (87.5); 2.5025 (61.0); 2.4979 (27.8); 2.3729 (0.8); 2.3385 (0.4); 2.3339 (0.5); 2.3293 (0.4); 1.6475 (10.6); 1.6301 (10.5) 505.2 I-115 [00259] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3679 (2.6); 9.3512 (2.7); 8.2462 (13.6); 8.1600 (16.0); 7.9753 (4.0); 7.9715 (6.9); 7.9677 (4.2); 7.6578 (2.3); 7.6525 (5.4); 7.6481 (4.3); 7.6405 (4.3); 7.6373 (4.7); 7.5309 (3.3); 7.3476 (6.9); 7.1643 (3.4); 6.0741 (0.4); 6.0567 (1.9); 6.0396 (2.9); 6.0225 (1.9); 6.0048 (0.4); 3.3529 (0.9); 3.3379 (166.7); 3.2565 (2.3); 3.0306 (2.2); 2.6775 (0.4); 2.6729 (0.5); 2.6683 (0.4); 2.5433 (85.8); 2.5300 (0.7); 2.5264 (1.2); 2.5217 (1.7); 2.5130 (28.9); 2.5085 (61.7); 2.5039 (82.2); 2.4993 (57.5); 2.4947 (26.4); 2.3353 (0.3); 2.3307 (0.5); 2.3260 (0.3); 1.6298 (11.5); 1.6123 (11.4) 517.2 I-116 [00260] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.7494 (2.5); 9.7329 (2.6); 8.5652 (3.6); 8.5609 (5.8); 8.5567 (4.4); 8.5179 (5.3); 8.4380 (3.0); 8.4340 (4.9); 8.2803 (0.4); 8.2714 (12.9); 8.1760 (0.4); 8.1635 (16.0); 6.1319 (0.4); 6.1150 (1.8); 6.0979 (2.8); 6.0808 (1.8); 6.0632 (0.4); 3.3423 (131.7); 3.2556 (2.3); 3.1240 (0.3); 3.0304 (2.3); 2.7162 (0.8); 2.6760 (0.4); 2.5693 (0.4); 2.5466 (216.1); 2.5296 (1.3); 2.5250 (1.7); 2.5161 (25.4); 2.5117 (52.9); 2.5071 (69.6); 2.5025 (48.7); 2.4980 (22.3); 2.3725 (0.8); 2.3339 (0.4); 2.0793 (0.6); 1.6634 (10.7); 1.6460 (10.8) 537.2 I-117 [00261] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5445 (1.9); 9.5277 (2.0); 8.2525 (16.0); 8.1726 (0.3); 8.1672 (12.4); 7.9576 (2.8); 7.3331 (3.0); 7.1945 (7.0); 7.0560 (3.3); 6.1005 (1.4); 6.0833 (2.2); 6.0661 (1.4); 3.3451 (73.1); 3.3282 (1.2); 3.3149 (0.6); 3.2516 (1.6); 3.0331 (1.6); 2.7159 (0.5); 2.5674 (0.3); 2.5667 (0.4); 2.5599 (0.8); 2.5566 (2.2); 2.5520 (4.7); 2.5466 (145.8); 2.5298 (1.5); 2.5253 (1.0); 2.5163 (13.4); 2.5117 (28.0); 2.5071 (37.5); 2.5025 (26.4); 2.4979 (12.2); 2.4861 (0.5); 2.4822 (0.5); 2.3723 (0.5); 2.0794 (0.4); 1.6541 (8.3); 1.6366 (8.4) 471.3 I-118 [00262] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4507 (2.5); 9.4340 (2.6); 8.2548 (12.5); 8.1623 (16.0); 8.1581 (4.2); 8.1541 (6.3); 8.1503 (3.8); 8.0796 (0.3); 8.0756 (0.5); 8.0720 (0.4); 7.9129 (3.7); 7.8269 (3.4); 7.8243 (3.9); 7.8217 (3.4); 6.0844 (0.4); 6.0672 (1.7); 6.0501 (2.7); 6.0330 (1.8); 6.0156 (0.4); 3.3430 (87.5); 3.2563 (2.2); 3.0324 (2.1); 2.7163 (0.6); 2.6808 (0.4); 2.6761 (0.5); 2.6715 (0.4); 2.5675 (0.3); 2.5466 (184.7); 2.5297 (1.4); 2.5249 (1.9); 2.5162 (28.2); 2.5117 (58.9); 2.5072 (77.9); 2.5025 (54.7); 2.4980 (25.3); 2.3725 (0.6); 2.3386 (0.3); 2.3340 (0.4); 2.3292 (0.3); 1.6382 (10.5); 1.6207 (10.4) 535.2 I-119 [00263] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3454 (2.2); 9.3287 (2.2); 8.2497 (11.8); 8.1641 (16.0); 7.5666 (9.8); 7.5610 (10.1); 7.5316 (6.0); 7.3482 (13.1); 7.2539 (2.4); 7.2484 (4.5); 7.2429 (2.3); 7.1649 (6.4); 6.0914 (0.3); 6.0746 (1.6); 6.0575 (2.4); 6.0403 (1.6); 6.0231 (0.3); 3.3583 (1.2); 3.3444 (125.0); 3.3227 (0.4); 3.2593 (1.8); 3.0335 (1.8); 2.7160 (0.8); 2.5608 (1.2); 2.5468 (244.8); 2.5353 (1.2); 2.5298 (0.8); 2.5251 (1.2); 2.5163 (17.1); 2.5118 (36.4); 2.5072 (48.8); 2.5026 (34.2); 2.4980 (15.6); 2.3724 (0.8); 2.0795 (0.3); 1.6419 (9.4); 1.6244 (9.3) 503.3 I-120 [00264] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6555 (2.6); 9.6388 (2.7); 8.4831 (3.5); 8.4795 (6.5); 8.4760 (3.8); 8.2692 (12.8); 8.1688 (16.0); 8.1645 (4.5); 8.1050 (3.9); 6.1352 (0.4); 6.1180 (1.8); 6.1009 (2.8); 6.0837 (1.8); 6.0663 (0.4); 3.3692 (31.1); 3.3420 (185.0); 3.3138 (0.5); 3.2560 (2.4); 3.1937 (0.6); 3.0321 (2.3); 2.6762 (0.4); 2.5466 (31.8); 2.5297 (1.2); 2.5250 (1.8); 2.5163 (26.4); 2.5119 (55.1); 2.5073 (72.9); 2.5027 (51.2); 2.4982 (23.8); 2.3341 (0.4); 1.6662 (10.7); 1.6488 (10.7) 533.3 I-121 [00265] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.7001 (2.8); 9.6835 (2.8); 8.4829 (4.0); 8.4787 (6.3); 8.4743 (4.3); 8.3969 (4.0); 8.3931 (6.9); 8.3894 (3.8); 8.2673 (13.9); 8.2076 (3.8); 8.2032 (6.3); 8.1988 (3.4); 8.1632 (16.0); 7.5556 (2.3); 7.4256 (5.3); 7.2958 (2.8); 6.1219 (0.4); 6.1050 (2.0); 6.0879 (3.0); 6.0708 (2.0); 6.0536 (0.4); 3.3860 (0.3); 3.3455 (263.2); 3.3083 (0.5); 3.2561 (2.5); 3.1446 (0.3); 3.0315 (2.4); 2.7163 (0.8); 2.6807 (0.4); 2.6761 (0.5); 2.6715 (0.4); 2.5465 (211.9); 2.5336 (0.7); 2.5296 (1.7); 2.5247 (2.4); 2.5161 (33.2); 2.5117 (68.5); 2.5071 (89.8); 2.5025 (62.8); 2.4980 (28.8); 2.3727 (0.7); 2.3384 (0.4); 2.3339 (0.5); 2.3294 (0.4); 1.6578 (11.7); 1.6404 (11.6) 519.3 I-122 [00266] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.2063 (2.5); 9.1895 (2.5); 8.7987 (0.7); 8.7879 (1.9); 8.7763 (1.9); 8.7652 (0.6); 8.2543 (0.5); 8.2455 (16.0); 8.2394 (13.4); 7.6456 (3.7); 7.6411 (5.5); 7.6368 (4.0); 7.4629 (3.2); 7.4592 (5.9); 7.4554 (3.4); 7.3469 (3.5); 7.3425 (5.7); 7.3381 (3.2); 6.0455 (0.4); 6.0284 (1.8); 6.0113 (2.7); 5.9941 (1.8); 5.9768 (0.4); 3.3491 (197.9); 2.8119 (13.7); 2.8004 (13.5); 2.7160 (0.6); 2.6760 (0.4); 2.5637 (0.4); 2.5597 (0.7); 2.5542 (2.5); 2.5466 (195.7); 2.5348 (0.8); 2.5297 (1.0); 2.5249 (1.6); 2.5163 (23.9); 2.5117 (50.6); 2.5072 (67.3); 2.5025 (46.8); 2.4979 (21.0); 2.3724 (0.6); 2.3340 (0.4); 2.0790 (0.4); 2.0293 (0.5); 2.0167 (1.2); 2.0083 (1.2); 2.0045 (0.8); 1.9959 (2.4); 1.9875 (0.8); 1.9833 (1.3); 1.9749 (1.2); 1.9623 (0.6); 1.6149 (10.6); 1.5975 (10.5); 1.0246 (1.5); 1.0135 (4.0); 1.0079 (4.3); 1.0038 (2.0); 0.9975 (2.1); 0.9925 (4.2); 0.9869 (4.1); 0.9767 (1.8); 0.7842 (1.9); 0.7736 431.3 (4.4); 0.7683 (4.4); 0.7612 (4.1); 0.7560 (4.7); 0.7446 (1.4) I-123 [00267] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6320 (2.3); 9.6154 (2.4); 8.6197 (16.0); 8.5192 (3.9); 8.4001 (3.8); 8.3156 (0.4); 8.2498 (3.9); 7.3864 (1.7); 7.2483 (4.2); 7.1102 (2.0); 6.0540 (0.3); 6.0365 (1.7); 6.0194 (2.6); 6.0023 (1.8); 5.9851 (0.3); 5.7555 (2.0); 3.3255 (95.0); 3.0351 (0.5); 3.0232 (1.1); 3.0156 (1.2); 3.0105 (0.7); 3.0038 (2.3); 2.9958 (0.8); 2.9917 (1.2); 2.9840 (1.2); 2.9721 (0.6); 2.6809 (0.3); 2.6763 (0.7); 2.6717 (1.0); 2.6670 (0.7); 2.6625 (0.4); 2.5252 (3.4); 2.5205 (5.0); 2.5118 (59.4); 2.5073 (123.3); 2.5027 (162.0); 2.4981 (113.4); 2.4935 (52.6); 2.3341 (0.7); 2.3296 (1.0); 2.3249 (0.7); 2.1157 (0.5); 2.1036 (1.1); 2.0949 (1.2); 2.0917 (0.9); 2.0829 (2.3); 2.0707 (1.3); 2.0621 (1.2); 2.0498 (0.6); 1.6173 (9.2); 1.5998 (9.1); 1.2347 (0.6); 1.2233 (0.5); 1.2119 (1.7); 1.1996 (2.7); 519.0 1.1975 (2.7); 1.1899 (3.2); 1.1790 (2.2); 1.1686 (0.9); 1.1558 (0.8); 1.1428 (0.5); 1.1357 (0.6); 1.1288 (1.1); 1.1142 (3.3); 1.1090 (2.7); 1.0945 (3.1); 1.0896 (2.2); 1.0872 (2.3); 1.0723 (0.5); 1.0565 (0.4); 1.0372 (3.0); 1.0334 (3.6); 1.0164 (3.0); 1.0125 (3.6); 0.9951 (0.5); 0.9173 (0.4); 0.9134 (0.5); 0.9060 (0.5); 0.9010 (0.5); 0.8911 (1.6); 0.8836 (1.4); 0.8753 (2.3); 0.8714 (2.3); 0.8667 (1.8); 0.8593 (1.2); 0.8548 (1.5); 0.8440 (0.4); 0.8395 (0.6); 0.8318 (0.4); 0.1459 (1.3); 0.0218 (0.4); 0.0166 (0.7); 0.0079 (11.7); −0.0002 (321.7); −0.0086 (10.6); −0.0153 (0.9); −0.0196 (0.5); −0.1497 (1.2) I-124 [00268] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4195 (1.3); 9.4028 (1.3); 8.3156 (0.6); 8.2120 (0.5); 8.1729 (1.9); 8.1691 (3.1); 8.1653 (2.0); 7.9052 (1.9); 7.8388 (1.8); 7.8362 (1.9); 6.0506 (0.8); 6.0334 (1.3); 6.0162 (0.8); 3.3253 (55.6); 2.6804 (0.6); 2.6758 (1.2); 2.6712 (1.7); 2.6667 (1.2); 2.6621 (0.6); 2.5247 (5.2); 2.5199 (8.1); 2.5112 (103.9); 2.5068 (211.6); 2.5023 (275.2); 2.4977 (194.6); 2.4932 (92.0); 2.3301 (16.0); 1.6146 (5.0); 1.5971 (5.1); 1.0766 (0.4); 1.0705 (0.4); 1.0585 (0.7); 1.0461 (0.4); 1.0401 (0.4); 0.5261 (0.4); 0.5115 (1.6); 0.4946 (1.5); 0.4816 (0.5); 0.2673 (1.0); 0.1459 (2.1); 0.0079 (17.6); −0.0001 (488.9); −0.0085 (18.7); −0.0345 (0.4); −0.1496 (2.1) 589.0 I-125 [00269] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4324 (1.4); 9.4155 (1.5); 8.2481 (1.6); 8.1788 (1.9); 8.1750 (3.3); 8.1713 (2.0); 7.9063 (2.1); 7.8432 (1.9); 7.8408 (2.1); 6.0594 (1.0); 6.0423 (1.6); 6.0250 (1.0); 4.6151 (1.7); 3.3252 (59.9); 2.6762 (0.5); 2.6717 (0.6); 2.6672 (0.5); 2.5251 (2.3); 2.5203 (3.6); 2.5117 (40.2); 2.5073 (81.6); 2.5028 (106.6); 2.4982 (75.5); 2.4937 (35.9); 2.3366 (16.0); 2.0747 (3.3); 1.6180 (5.5); 1.6006 (5.5); 0.1457 (0.8); 0.0078 (7.3); −0.0002 (181.4); −0.0087 (6.9); −0.1498 (0.8) 574.0 I-126 [00270] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4179 (1.2); 9.4009 (1.2); 8.3156 (0.5); 8.1724 (1.6); 8.1687 (2.7); 8.1649 (1.7); 7.9069 (1.8); 7.8377 (1.6); 7.8352 (1.7); 6.0461 (0.9); 6.0288 (1.4); 6.0115 (0.9); 3.3250 (219.6); 3.0312 (0.4); 2.6802 (0.5); 2.6756 (1.1); 2.6710 (1.5); 2.6664 (1.1); 2.6618 (0.5); 2.5246 (4.6); 2.5199 (6.9); 2.5112 (90.7); 2.5067 (188.8); 2.5021 (248.6); 2.4975 (174.0); 2.4929 (80.8); 2.3291 (16.0); 1.6126 (4.8); 1.5952 (4.7); 1.1782 (3.5); 1.1627 (3.4); 0.1458 (2.1); 0.0273 (0.3); 0.0079 (18.8); −0.0002 (519.2); −0.0087 (16.9); −0.0257 (0.5); −0.1498 (2.1) 577.0 I-127 [00271] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.2448 (1.4); 9.2276 (1.4); 8.3155 (0.4); 8.2803 (2.9); 7.5807 (3.0); 7.5771 (2.2); 7.5662 (2.0); 7.2953 (2.0); 6.0553 (1.0); 6.0380 (1.6); 6.0207 (1.0); 3.3247 (83.5); 3.1561 (0.6); 3.0141 (9.7); 2.6802 (0.3); 2.6758 (0.7); 2.6712 (0.9); 2.6668 (0.7); 2.6622 (0.3); 2.5248 (3.0); 2.5200 (4.5); 2.5113 (57.7); 2.5069 (118.2); 2.5024 (154.4); 2.4978 (108.9); 2.4933 (51.3); 2.3258 (16.0); 2.0726 (0.6); 2.0641 (0.6); 2.0606 (0.5); 2.0517 (1.2); 2.0391 (0.7); 2.0309 (0.7); 2.0181 (0.3); 1.6162 (5.4); 1.5987 (5.4); 1.0562 (0.6); 1.0452 (2.0); 1.0396 (2.2); 1.0292 (1.0); 1.0243 (2.1); 1.0187 (2.1); 1.0086 (0.8); 0.8936 (0.6); 0.8701 (1.2); 0.8539 (0.9); 0.8372 (0.5); 0.8116 (0.9); 0.8011 (2.2); 0.7959 (2.2); 0.7888 (2.2); 0.7838 (2.2); 0.7726 (0.9); 0.7657 (0.5); 0.7512 (0.5); 0.7407 (0.9); 0.7366 (0.9); 0.7319 (1.0); 0.7237 (1.1); 0.7139 (1.0); 0.7041 (0.8); 0.6942 (0.5); 0.1458 (0.8); 0.0079 (7.2); −0.0002 (198.4); −0.0085 (6.9); −0.1497 (0.9) 353.2 I-128 [00272] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.2471 (1.5); 9.2300 (1.5); 8.3156 (0.5); 7.5778 (3.3); 7.5742 (2.8); 7.5650 (2.3); 7.2959 (2.2); 6.0468 (1.0); 6.0296 (1.5); 6.0121 (1.0); 3.3729 (1.3); 3.3695 (1.3); 3.3236 (102.3); 2.6756 (1.2); 2.6710 (1.6); 2.6665 (1.2); 2.5242 (6.6); 2.5107 (104.5); 2.5065 (202.3); 2.5021 (259.4); 2.4976 (186.1); 2.4934 (90.8); 2.3259 (16.0); 2.0729 (0.6); 2.0644 (0.7); 2.0521 (1.3); 2.0399 (0.8); 2.0314 (0.7); 2.0187 (0.4); 1.6135 (5.6); 1.5960 (5.6); 1.0744 (0.6); 1.0686 (0.5); 1.0566 (1.4); 1.0453 (2.6); 1.0397 (2.8); 1.0292 (1.3); 1.0244 (2.4); 1.0189 (2.4); 1.0088 (0.8); 0.8135 (0.9); 0.8028 (2.3); 0.7978 (2.3); 0.7906 (2.3); 0.7856 (2.3); 0.7746 (0.7); 0.5249 (0.6); 0.5111 (1.9); 0.4942 (1.8); 0.4810 (0.6); 0.2681 (1.2); 0.1458 (1.5); 0.0078 (14.7); −0.0002 (321.5); −0.0084 (13.8); −0.0382 (0.4); −0.1497 (1.5) 549.2 I-129 [00273] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.2473 (1.5); 9.2302 (1.5); 7.5786 (3.2); 7.5647 (2.3); 7.2964 (2.3); 6.0449 (1.1); 6.0276 (1.7); 6.0103 (1.1); 3.5037 (0.9); 3.3255 (52.0); 3.2156 (0.6); 2.6761 (0.5); 2.6718 (0.7); 2.6671 (0.5); 2.5248 (2.7); 2.5112 (48.0); 2.5071 (94.0); 2.5027 (120.9); 2.4982 (86.8); 2.4942 (42.4); 2.3253 (16.0); 2.0736 (0.7); 2.0648 (0.7); 2.0525 (1.3); 2.0400 (0.8); 2.0315 (0.7); 2.0190 (0.4); 1.6125 (5.8); 1.5950 (5.8); 1.1549 (1.2); 1.0566 (0.7); 1.0457 (2.2); 1.0401 (2.4); 1.0295 (1.1); 1.0248 (2.2); 1.0194 (2.2); 1.0092 (0.8); 0.8132 (0.9); 0.8029 (2.4); 0.7980 (2.4); 0.7907 (2.3); 0.7859 (2.4); 0.7745 (0.7); 0.1460 (0.6); 0.0077 (5.6); −0.0002 (118.0); −0.0084 (4.5); −0.1496 (0.6) 523.2 I-130 [00274] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4047 (3.6); 9.3884 (3.6); 8.6652 (16.0); 8.3157 (14.4); 7.9497 (8.1); 7.7507 (6.1); 7.6035 (6.6); 7.5811 (6.2); 7.5418 (3.5); 7.4647 (3.2); 7.3585 (7.2); 7.1753 (3.6); 6.0616 (0.6); 6.0445 (2.4); 6.0274 (3.6); 6.0104 (2.4); 5.9932 (0.6); 3.3272 (169.1); 2.6714 (1.4); 2.6670 (1.1); 2.5402 (1.2); 2.5068 (178.6); 2.5025 (228.6); 2.4982 (169.7); 2.3335 (1.0); 2.3293 (1.4); 2.3251 (1.0); 2.0745 (1.9); 1.6309 (14.0); 1.6134 (13.9); 0.1458 (1.0); 0.0075 (9.9); −0.0002 (205.9); −0.1497 (1.0) 473.1 I-131 [00275] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4129 (2.4); 9.3965 (2.5); 8.6658 (16.0); 8.3177 (11.2); 7.8019 (1.5); 7.7985 (1.8); 7.7963 (1.8); 7.7929 (1.6); 7.7789 (1.5); 7.7755 (1.9); 7.7732 (1.7); 7.7698 (1.6); 7.7088 (3.5); 7.6521 (1.6); 7.6314 (1.6); 6.0537 (0.4); 6.0366 (1.7); 6.0196 (2.6); 6.0026 (1.7); 5.9852 (0.4); 3.3281 (89.1); 3.3141 (0.5); 2.6770 (0.5); 2.6725 (0.6); 2.6680 (0.4); 2.5260 (1.9); 2.5211 (3.3); 2.5125 (39.4); 2.5081 (79.0); 2.5036 (101.5); 2.4990 (70.6); 2.4944 (32.4); 2.3350 (0.4); 2.3304 (0.6); 2.3258 (0.4); 1.6307 (10.3); 1.6132 (10.3); 0.1459 (0.5); 0.0163 (0.3); 0.0079 (4.9); −0.0002 (128.0); −0.0085 (3.9); −0.0142 (0.4); −0.1497 (0.5) 427.1 I-132 [00276] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5202 (2.5); 9.5037 (2.6); 8.6160 (16.0); 8.3431 (0.4); 8.3151 (0.5); 8.2877 (3.7); 8.2841 (6.5); 8.2805 (3.6); 7.9631 (0.4); 7.9529 (2.8); 7.9479 (3.9); 7.9443 (3.1); 7.8847 (3.3); 7.8805 (4.1); 7.8755 (2.6); 7.8411 (1.2); 7.6194 (2.9); 7.4368 (6.2); 7.2542 (3.1); 6.0387 (0.4); 6.0215 (1.8); 6.0044 (2.8); 5.9872 (1.8); 5.9697 (0.4); 4.3383 (0.9); 3.3395 (2.4); 3.3260 (151.5); 3.3213 (38.1); 2.6804 (0.4); 2.6760 (0.9); 2.6714 (1.2); 2.6668 (0.9); 2.6623 (0.4); 2.5249 (3.9); 2.5202 (6.2); 2.5115 (77.0); 2.5070 (156.0); 2.5025 (201.6); 2.4979 (140.7); 2.4933 (65.1); 2.3382 (0.4); 2.3339 (0.9); 2.3293 (1.2); 2.3247 (0.9); 2.1126 (0.5); 2.1004 (1.2); 2.0916 (1.3); 2.0797 (2.4); 2.0676 (1.4); 2.0590 (1.3); 2.0468 (0.6); 1.9889 (1.2); 1.7678 (0.3); 1.6074 (9.7); 1.5900 (9.7); 1.2352 (0.4); 1.1931 (0.4); 1.1754 (0.7); 1.1576 (0.4); 1.0678 (0.3); 1.0546 (0.5); 1.0374 (3.7); 1.0336 (4.0); 509.1 1.0169 (3.7); 1.0126 (3.7); 0.9975 (0.6); 0.9851 (0.4); 0.9107 (0.5); 0.9022 (0.6); 0.8985 (0.5); 0.8907 (1.6); 0.8862 (1.8); 0.8730 (3.0); 0.8688 (2.7); 0.8648 (2.2); 0.8603 (1.6); 0.8554 (1.4); 0.8457 (0.5); 0.8410 (0.5); 0.8330 (0.4); 0.1459 (1.1); 0.0079 (10.0); −0.0002 (275.7); −0.0086 (9.2); −0.0151 (0.8); −0.1496 (1.1) I-133 [00277] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5379 (2.4); 9.5213 (2.4); 8.6156 (16.0); 8.5838 (0.7); 8.3144 (1.0); 8.2516 (3.3); 8.2480 (6.0); 8.2444 (3.3); 7.9605 (2.5); 7.9554 (3.4); 7.9516 (2.7); 7.8464 (2.8); 7.8419 (3.6); 7.8369 (2.5); 7.6314 (2.9); 7.4488 (6.2); 7.2662 (3.1); 6.0367 (0.3); 6.0195 (1.6); 6.0023 (2.5); 5.9852 (1.7); 5.9679 (0.3); 3.3252 (432.5); 3.3076 (0.9); 3.0174 (0.5); 3.0055 (1.1); 2.9978 (1.2); 2.9933 (1.0); 2.9861 (2.2); 2.9780 (0.8); 2.9740 (1.2); 2.9663 (1.2); 2.9541 (0.5); 2.6802 (0.7); 2.6757 (1.4); 2.6711 (2.0); 2.6665 (1.4); 2.6619 (0.7); 2.5647 (0.3); 2.5246 (5.5); 2.5199 (8.2); 2.5112 (111.3); 2.5067 (229.2); 2.5021 (304.1); 2.4975 (218.5); 2.4929 (103.2); 2.3381 (0.6); 2.3336 (1.4); 2.3290 (1.9); 2.3244 (1.4); 2.3199 (0.6); 2.1136 (0.5); 2.1015 (1.1); 2.0928 (1.2); 2.0897 (0.9); 2.0808 (2.3); 2.0737 (0.9); 2.0687 (1.3); 2.0601 (1.2); 2.0479 (0.6); 1.6086 (8.8); 1.5912 (8.8); 1.3597 (0.4); 1.3424 (0.4); 1.2297 (0.4); 1.2180 (0.4); 1.2072 (1.4); 1.1940 (2.5); 1.1854 (2.9); 1.1744 (1.9); 1.1646 535.0 (0.7); 1.1521 (0.5); 1.1390 (0.3); 1.1269 (0.5); 1.1210 (0.8); 1.1073 (3.0); 1.1012 (2.4); 1.0878 (2.8); 1.0823 (1.9); 1.0794 (2.0); 1.0655 (0.5); 1.0566 (0.6); 1.0382 (3.0); 1.0340 (3.8); 1.0175 (3.2); 1.0131 (3.6); 0.9966 (0.5); 0.9114 (0.5); 0.9040 (0.5); 0.8995 (0.6); 0.8884 (1.6); 0.8819 (1.4); 0.8746 (2.5); 0.8701 (2.2); 0.8663 (1.7); 0.8588 (1.2); 0.8539 (1.5); 0.8433 (0.4); 0.8390 (0.5); 0.8314 (0.4); 0.1459 (1.3); 0.0080 (10.4); −0.0002 (329.6); −0.0086 (10.4); −0.0181 (0.6); −0.1496 (1.3) I-134 [00278] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.7031 (3.1); 9.6868 (3.2); 8.6708 (16.0); 8.4784 (4.0); 8.4743 (6.7); 8.4701 (4.3); 8.3880 (4.1); 8.3844 (7.0); 8.3809 (4.0); 8.3383 (14.6); 8.2108 (4.0); 8.2064 (6.7); 8.2021 (3.6); 7.5579 (2.5); 7.4280 (5.7); 7.2981 (2.9); 6.0909 (0.4); 6.0738 (2.1); 6.0569 (3.1); 6.0400 (2.1); 6.0226 (0.4); 3.3366 (331.1); 2.7165 (0.8); 2.6849 (0.4); 2.6808 (0.9); 2.6763 (1.2); 2.6718 (0.9); 2.6672 (0.4); 2.5466 (193.9); 2.5296 (3.6); 2.5247 (5.6); 2.5162 (78.1); 2.5118 (160.4); 2.5073 (211.0); 2.5028 (149.3); 2.4983 (70.3); 2.3729 (0.8); 2.3432 (0.4); 2.3386 (0.9); 2.3341 (1.2); 2.3295 (0.9); 2.0799 (1.5); 1.6495 (12.4); 1.6321 (12.3) 473.0 I-135 [00279] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5169 (2.6); 9.5006 (2.6); 8.6705 (16.0); 8.3946 (3.8); 8.3912 (7.1); 8.3877 (4.1); 8.3324 (13.2); 8.2595 (3.6); 8.1181 (3.4); 8.1157 (3.8); 8.1134 (3.3); 6.0743 (0.4); 6.0572 (1.9); 6.0403 (2.8); 6.0233 (1.9); 6.0061 (0.4); 3.3401 (227.8); 2.7161 (0.6); 2.6854 (0.4); 2.6807 (0.8); 2.6762 (1.1); 2.6716 (0.8); 2.6670 (0.4); 2.5466 (173.0); 2.5296 (3.1); 2.5250 (4.8); 2.5163 (66.8); 2.5118 (139.7); 2.5072 (185.9); 2.5026 (130.0); 2.4980 (59.6); 2.3727 (0.6); 2.3431 (0.4); 2.3385 (0.8); 2.3340 (1.1); 2.3294 (0.8); 2.3248 (0.4); 2.0798 (0.8); 1.6419 (11.4); 1.6245 (11.3) 434.1 I-136 [00280] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.7078 (2.2); 9.6915 (2.3); 8.6638 (16.0); 8.3497 (3.0); 8.3461 (5.6); 8.3425 (3.2); 8.3299 (10.6); 8.3147 (0.4); 8.1842 (2.6); 8.1791 (3.3); 8.1751 (2.6); 7.9063 (2.5); 7.9016 (3.5); 7.8971 (2.4); 7.6661 (2.9); 7.5469 (1.9); 7.4842 (6.3); 7.4170 (4.5); 7.3022 (3.1); 7.2872 (2.3); 6.0799 (1.5); 6.0630 (2.3); 6.0460 (1.5); 6.0289 (0.3); 3.3255 (143.1); 2.6762 (0.6); 2.6716 (0.8); 2.6670 (0.6); 2.5251 (2.3); 2.5204 (3.4); 2.5118 (46.8); 2.5072 (96.0); 2.5026 (127.1); 2.4980 (90.7); 2.4934 (42.3); 2.3341 (0.6); 2.3295 (0.8); 2.3249 (0.6); 2.0745 (14.4); 1.6516 (9.2); 1.6341 (9.1); 0.1459 (0.5); 0.0080 (3.8); −0.0002 (119.3); −0.0086 (3.6); −0.1496 (0.4) 505.0 I-137 [00281] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5262 (2.2); 9.5094 (2.2); 8.7907 (0.6); 8.7800 (1.7); 8.7686 (1.6); 8.7574 (0.5); 8.3149 (1.5); 8.2485 (12.9); 8.2433 (16.0); 7.9488 (3.1); 7.3242 (3.2); 7.1856 (7.3); 7.0471 (3.4); 6.0805 (1.4); 6.0633 (2.2); 6.0460 (1.4); 3.3795 (0.4); 3.3253 (548.1); 2.8073 (10.2); 2.7958 (10.2); 2.6800 (1.0); 2.6756 (2.1); 2.6711 (2.9); 2.6665 (2.1); 2.6620 (1.0); 2.5739 (0.4); 2.5609 (0.6); 2.5245 (8.1); 2.5197 (12.1); 2.5111 (159.0); 2.5066 (323.5); 2.5021 (427.5); 2.4975 (308.8); 2.4930 (148.2); 2.3381 (0.8); 2.3334 (1.9); 2.3289 (2.7); 2.3243 (2.0); 2.3200 (0.9); 2.0742 (0.3); 1.6380 (8.5); 1.6205 (8.5); 0.1459 (0.6); 0.0080 (4.6); −0.0001 (150.6); −0.0084 (5.4); −0.1496 (0.7) 457.2 I-138 [00282] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 10.0999 (1.1); 10.0835 (1.2); 9.1126 (5.0); 9.1085 (5.1); 8.6777 (2.0); 8.6664 (7.2); 8.3574 (5.5); 6.1485 (0.8); 6.1315 (1.2); 6.1144 (0.8); 3.3253 (64.8); 2.6757 (0.4); 2.6711 (0.5); 2.6665 (0.4); 2.5416 (45.0); 2.5332 (0.5); 2.5297 (0.5); 2.5248 (1.4); 2.5200 (2.2); 2.5113 (31.0); 2.5068 (63.7); 2.5022 (84.0); 2.4976 (59.9); 2.4931 (28.2); 2.3336 (0.4); 2.3291 (0.5); 2.3245 (0.4); 2.0753 (16.0); 1.6856 (4.7); 1.6682 (4.6); 0.0080 (1.3); −0.0002 (41.2); −0.0086 (1.2) 589.2 I-139 [00283] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6244 (2.4); 9.6080 (2.4); 8.6628 (16.0); 8.3382 (11.8); 7.9483 (7.4); 7.9460 (7.4); 7.6459 (7.9); 7.6434 (7.7); 6.0506 (0.4); 6.0333 (1.7); 6.0163 (2.6); 5.9993 (1.7); 5.9818 (0.4); 3.3307 (304.8); 2.6805 (0.6); 2.6759 (1.2); 2.6713 (1.7); 2.6666 (1.2); 2.6621 (0.6); 2.5416 (1.3); 2.5248 (4.3); 2.5200 (6.9); 2.5114 (101.6); 2.5069 (209.4); 2.5023 (274.8); 2.4977 (193.4); 2.4931 (89.4); 2.3383 (0.5); 2.3337 (1.2); 2.3291 (1.6); 2.3245 (1.2); 2.3201 (0.5); 2.0749 (8.4); 1.6299 (10.6); 1.6125 (10.6); −0.0002 (0.8) 444.1 I-140 [00284] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5663 (2.3); 9.5496 (2.4); 8.7868 (0.6); 8.7764 (1.8); 8.7648 (1.8); 8.7540 (0.6); 8.3607 (3.0); 8.3568 (5.7); 8.3530 (3.4); 8.3151 (1.0); 8.2504 (3.2); 8.2464 (16.0); 8.2416 (4.4); 8.2344 (12.1); 8.2299 (4.4); 8.2258 (4.9); 8.2214 (2.5); 8.0817 (0.8); 8.0751 (7.5); 8.0702 (2.3); 8.0583 (2.4); 8.0533 (8.8); 8.0469 (1.0); 7.7455 (1.0); 7.7390 (8.5); 7.7340 (2.5); 7.7221 (2.2); 7.7172 (7.6); 7.7108 (0.8); 6.0617 (1.5); 6.0446 (2.2); 6.0275 (1.5); 6.0106 (0.3); 4.0381 (0.7); 4.0202 (0.8); 3.7934 (0.5); 3.7768 (0.5); 3.3271 (442.8); 2.8095 (11.1); 2.7980 (11.0); 2.6902 (0.5); 2.6804 (0.9); 2.6761 (1.9); 2.6716 (2.6); 2.6670 (1.9); 2.6626 (0.9); 2.5250 (8.2); 2.5203 (12.2); 2.5116 (157.7); 2.5072 (322.1); 2.5026 (421.1); 2.4980 (297.2); 2.4935 (139.8); 2.3381 (0.8); 2.3339 (1.8); 2.3294 (2.5); 2.3248 (1.8); 2.3203 (0.8); 2.0116 565.1 (1.7); 2.0000 (0.4); 1.9891 (3.2); 1.9090 (1.2); 1.6300 (8.5); 1.6126 (8.5); 1.5902 (0.4); 1.3363 (0.7); 1.2984 (0.4); 1.2590 (0.6); 1.2342 (1.2); 1.2252 (1.1); 1.1933 (0.9); 1.1755 (1.7); 1.1577 (0.8); 0.8887 (1.9); 0.8718 (1.8); −0.0002 (1.7) I-141 [00285] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5758 (2.5); 9.5590 (2.6); 8.3678 (3.4); 8.3639 (6.5); 8.3600 (3.8); 8.3117 (0.6); 8.2487 (12.8); 8.2448 (7.4); 8.2400 (8.6); 8.2357 (6.0); 8.2308 (2.0); 8.1429 (16.0); 8.0843 (0.9); 8.0778 (8.8); 8.0727 (2.7); 8.0610 (2.9); 8.0558 (10.3); 8.0494 (1.1); 7.7477 (1.1); 7.7412 (9.8); 7.7361 (2.8); 7.7243 (2.6); 7.7193 (8.8); 7.7128 (0.9); 6.0921 (0.4); 6.0750 (1.6); 6.0579 (2.5); 6.0408 (1.6); 6.0235 (0.4); 3.3499 (798.7); 3.2874 (0.7); 3.2706 (0.6); 3.2294 (2.1); 3.0254 (1.9); 2.6830 (0.4); 2.6785 (0.9); 2.6739 (1.3); 2.6693 (0.9); 2.6647 (0.4); 2.5274 (4.2); 2.5227 (6.1); 2.5140 (70.4); 2.5094 (143.1); 2.5048 (192.1); 2.5002 (142.6); 2.4956 (69.2); 2.3408 (0.4); 2.3363 (0.9); 2.3317 (1.3); 2.3271 (0.9); 2.3226 (0.4); 1.6420 (9.4); 1.6246 (9.4); 0.1459 (0.9); 0.0081 (7.9); −0.0002 (224.7); −0.0085 (7.1); −0.1496 (0.9) 579.2 I-142 [00286] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4349 (2.8); 9.4185 (2.8); 8.6673 (16.0); 8.3205 (12.1); 8.3151 (0.6); 7.8463 (3.7); 7.8426 (6.1); 7.8388 (3.7); 7.7620 (3.6); 7.7595 (4.0); 7.7571 (3.5); 7.4921 (4.0); 6.0707 (0.4); 6.0536 (1.8); 6.0366 (2.8); 6.0195 (1.8); 6.0022 (0.4); 3.3294 (192.2); 2.6768 (0.7); 2.6722 (1.0); 2.6677 (0.7); 2.6631 (0.3); 2.5257 (3.3); 2.5209 (4.8); 2.5122 (57.6); 2.5078 (113.2); 2.5032 (145.5); 2.4986 (104.2); 2.4942 (49.8); 2.3392 (0.3); 2.3346 (0.7); 2.3300 (0.9); 2.3254 (0.6); 2.0748 (4.0); 1.8606 (2.0); 1.8483 (5.9); 1.8408 (6.5); 1.8294 (2.8); 1.7897 (0.4); 1.7078 (0.4); 1.6689 (3.1); 1.6566 (6.4); 1.6492 (6.6); 1.6407 (11.5); 1.6232 (11.0); 0.1459 (0.6); 0.0147 (0.4); 0.0080 (4.2); −0.0002 (129.7); −0.0085 (4.6); −0.1495 (0.6) 474.0 I-143 [00287] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5815 (2.6); 9.5651 (2.7); 8.6590 (12.4); 8.3597 (3.3); 8.3559 (6.1); 8.3522 (3.6); 8.3181 (10.2); 8.2536 (2.6); 8.2490 (5.7); 8.2448 (3.8); 8.2332 (4.0); 8.2293 (5.2); 8.2250 (2.5); 8.1456 (0.7); 8.0857 (0.9); 8.0790 (7.7); 8.0743 (2.5); 8.0622 (2.7); 8.0573 (9.1); 8.0509 (1.1); 7.8695 (0.5); 7.7501 (1.0); 7.7437 (8.4); 7.7391 (2.5); 7.7268 (2.3); 7.7221 (7.4); 7.7156 (0.8); 6.0618 (0.4); 6.0447 (1.6); 6.0278 (2.4); 6.0107 (1.6); 5.9933 (0.3); 4.0383 (0.7); 4.0205 (0.7); 3.3292 (318.5); 2.6766 (1.4); 2.6722 (2.0); 2.6676 (1.4); 2.5255 (6.1); 2.5206 (9.2); 2.5118 (118.0); 2.5076 (236.6); 2.5031 (308.5); 2.4986 (223.4); 2.4943 (109.4); 2.3344 (1.3); 2.3299 (1.9); 2.3254 (1.4); 2.0118 (0.5); 1.9893 (3.0); 1.6322 532.8 (9.5); 1.6147 (9.5); 1.3977 (16.0); 1.2350 (1.7); 1.1935 (0.8); 1.1757 (1.6); 1.1580 (0.8); 0.8889 (0.6); 0.8721 (0.6); 0.1460 (1.1); 0.0080 (7.9); −0.0001 (239.0); −0.0084 (8.1); −0.1496 (1.1) I-144 [00288] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5160 (3.3); 9.4997 (3.4); 8.6654 (16.0); 8.3245 (13.6); 8.3161 (0.6); 7.9186 (9.6); 7.9143 (9.8); 7.7731 (4.2); 6.0668 (0.5); 6.0496 (2.2); 6.0327 (3.3); 6.0157 (2.2); 5.9984 (0.5); 3.7277 (0.4); 3.3273 (170.7); 2.6767 (1.0); 2.6722 (1.3); 2.6677 (0.9); 2.6633 (0.4); 2.5256 (4.7); 2.5120 (80.8); 2.5077 (153.8); 2.5032 (196.7); 2.4987 (143.3); 2.4943 (69.9); 2.3346 (0.9); 2.3301 (1.3); 2.3256 (0.9); 1.6393 (13.1); 1.6219 (13.0); 0.1460 (0.5); 0.0076 (4.5); −0.0001 (111.6); −0.0085 (3.8); −0.1495 (0.5) 493.2 I-145 [00289] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4381 (2.5); 9.4214 (2.5); 8.3169 (4.7); 8.2531 (12.2); 8.1524 (3.5); 8.1486 (6.0); 8.1448 (3.7); 7.9112 (3.5); 7.8221 (3.2); 7.8195 (3.6); 7.8169 (3.1); 6.0883 (0.4); 6.0712 (1.7); 6.0541 (2.6); 6.0370 (1.7); 6.0198 (0.4); 3.3339 (194.8); 3.1713 (1.0); 3.0197 (16.0); 2.6810 (0.4); 2.6765 (0.9); 2.6719 (1.2); 2.6673 (0.9); 2.6627 (0.4); 2.5423 (8.2); 2.5254 (3.8); 2.5207 (5.8); 2.5120 (71.3); 2.5075 (143.2); 2.5029 (188.4); 2.4983 (137.7); 2.4938 (66.8); 2.3389 (0.4); 2.3344 (0.8); 2.3297 (1.2); 2.3252 (0.8); 2.3206 (0.4); 1.6385 (9.8); 1.6210 (9.8); 0.9118 (0.5); 0.8972 (1.1); 0.8868 (1.3); 0.8808 (1.7); 0.8734 (2.0); 0.8639 (1.2); 0.8584 (1.4); 0.8410 (0.8); 0.8323 (0.4); 0.8236 (0.4); 0.7838 (0.4); 0.7744 (0.7); 0.7602 (0.8); 0.7501 (1.5); 0.7457 (1.4); 0.7404 (1.7); 0.7331 (1.9); 0.7238 (1.8); 0.7134 (1.3); 0.7036 (0.8); 0.6978 (0.4); 0.6890 (0.5); −0.0002 (1.2) 561.1 I-146 [00290] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6893 (2.6); 9.6727 (2.6); 8.4782 (3.6); 8.4739 (5.5); 8.4696 (4.0); 8.3951 (3.4); 8.3913 (6.1); 8.3875 (3.3); 8.3193 (4.6); 8.2658 (12.8); 8.2056 (3.5); 8.2012 (5.8); 8.1967 (3.2); 7.5526 (2.0); 7.4227 (4.7); 7.2928 (2.4); 6.1280 (0.4); 6.1108 (1.7); 6.0937 (2.6); 6.0766 (1.7); 6.0591 (0.4); 3.3369 (159.7); 3.1698 (1.0); 3.0202 (16.0); 2.6817 (0.3); 2.6771 (0.7); 2.6726 (1.0); 2.6679 (0.7); 2.6632 (0.3); 2.5586 (0.4); 2.5578 (0.4); 2.5564 (0.5); 2.5527 (0.7); 2.5429 (98.4); 2.5349 (0.7); 2.5341 (0.6); 2.5333 (0.6); 2.5326 (0.6); 2.5303 (0.7); 2.5261 (3.0); 2.5215 (4.6); 2.5127 (57.2); 2.5082 (117.2); 2.5035 (155.5); 2.4989 (113.5); 2.4943 (54.5); 2.3395 (0.3); 2.3350 (0.7); 2.3304 (1.0); 2.3258 (0.7); 2.3211 (0.3); 2.0757 (0.5); 1.6584 (9.9); 1.6410 (9.9); 0.9112 (0.5); 0.8984 (1.1); 0.8919 (1.2); 0.8884 (1.2); 0.8810 (1.7); 0.8743 (2.1); 0.8606 (1.6); 0.8571 (1.3); 0.8432 (0.7); 545.1 0.8328 (0.4); 0.8244 (0.4); 0.7850 (0.4); 0.7757 (0.7); 0.7626 (0.8); 0.7505 (1.3); 0.7462 (1.4); 0.7413 (1.8); 0.7368 (2.2); 0.7333 (2.2); 0.7272 (2.0); 0.7167 (1.2); 0.7063 (0.7); 0.6979 (0.4); 0.6924 (0.5); −0.0002 (0.4) I-147 [00291] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6508 (2.6); 9.6341 (2.7); 8.4837 (3.6); 8.4800 (6.7); 8.4764 (3.8); 8.3277 (4.6); 8.2705 (12.7); 8.1635 (3.6); 8.1611 (3.4); 8.1060 (3.7); 6.1453 (0.4); 6.1280 (1.7); 6.1109 (2.6); 6.0937 (1.7); 6.0764 (0.4); 3.4035 (0.4); 3.3671 (32.6); 3.3475 (172.6); 3.3436 (210.3); 3.1911 (0.8); 3.1731 (1.0); 3.0239 (16.0); 2.6810 (0.6); 2.6764 (0.9); 2.6718 (0.7); 2.5468 (2.2); 2.5299 (2.9); 2.5252 (4.4); 2.5165 (53.5); 2.5120 (109.4); 2.5074 (145.3); 2.5028 (107.1); 2.4982 (52.4); 2.3388 (0.6); 2.3343 (0.9); 2.3297 (0.7); 2.0794 (2.1); 1.6699 (9.7); 1.6524 (9.7); 0.9162 (0.6); 0.9017 (1.1); 0.8920 (1.3); 0.8828 (1.8); 0.8782 (2.1); 0.8689 (1.3); 0.8647 (1.5); 0.8469 (0.8); 0.8378 (0.4); 0.8294 (0.4); 0.7873 (0.4); 0.7781 (0.7); 0.7646 (0.8); 0.7538 (1.4); 0.7491 (1.5); 0.7439 (1.7); 0.7391 (2.2); 0.7359 (2.1); 0.7293 (1.9); 0.7190 (1.2); 0.7090 (0.7); 0.7039 (0.4); 0.7000 (0.4); 0.6946 (0.5) 559.2 I-148 [00292] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3365 (2.5); 9.3198 (2.6); 8.3209 (4.7); 8.2469 (11.8); 7.5622 (10.2); 7.5567 (10.7); 7.5262 (6.1); 7.3428 (13.0); 7.2507 (2.7); 7.2453 (4.9); 7.2399 (2.5); 7.1595 (6.4); 6.0970 (0.4); 6.0798 (1.7); 6.0627 (2.6); 6.0455 (1.7); 6.0280 (0.4); 3.3403 (105.2); 3.3359 (136.8); 3.1726 (1.0); 3.0219 (16.0); 2.7122 (0.3); 2.6765 (0.6); 2.6720 (0.8); 2.6674 (0.6); 2.5520 (0.9); 2.5424 (79.8); 2.5254 (2.4); 2.5206 (3.7); 2.5119 (46.7); 2.5075 (93.2); 2.5030 (122.9); 2.4985 (91.3); 2.4941 (45.6); 2.3684 (0.4); 2.3344 (0.6); 2.3298 (0.8); 2.3253 (0.6); 2.0754 (0.5); 1.6411 (9.8); 1.6237 (9.8); 0.9158 (0.6); 0.8955 (1.9); 0.8884 (2.4); 0.8782 (2.0); 0.8716 (2.4); 0.8539 (0.9); 0.8447 (0.3); 0.8367 (0.4); 0.7872 (0.4); 0.7780 (0.6); 0.7656 (0.8); 0.7500 (2.3); 0.7418 (3.3); 0.7336 (2.4); 0.7262 (1.2); 0.7163 (0.7); 0.7030 (0.4); −0.0002 (0.6) 529.2 I-149 [00293] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5649 (2.3); 9.5483 (2.3); 8.3653 (3.3); 8.3614 (6.2); 8.3576 (3.7); 8.3164 (0.3); 8.3000 (4.4); 8.2550 (12.7); 8.2520 (6.8); 8.2475 (4.3); 8.2361 (4.3); 8.2323 (5.1); 8.2276 (2.6); 8.0827 (0.9); 8.0761 (8.2); 8.0711 (2.5); 8.0593 (2.7); 8.0542 (9.6); 8.0477 (1.0); 7.7484 (1.0); 7.7420 (9.4); 7.7369 (2.7); 7.7251 (2.5); 7.7200 (8.3); 7.7135 (0.8); 6.0802 (1.5); 6.0631 (2.3); 6.0459 (1.6); 6.0284 (0.4); 3.3354 (495.6); 3.1531 (1.0); 3.0148 (16.0); 2.7118 (0.5); 2.6809 (0.9); 2.6763 (1.9); 2.6717 (2.6); 2.6671 (1.9); 2.6625 (0.9); 2.5839 (0.3); 2.5421 (150.0); 2.5252 (8.6); 2.5205 (13.1); 2.5118 (156.7); 2.5073 (315.6); 2.5027 (415.5); 2.4980 (303.0); 2.4935 (146.1); 2.3686 (0.5); 2.3385 (0.9); 2.3341 (1.9); 2.3295 (2.6); 2.3249 (1.9); 2.3204 (0.8); 2.0752 (0.5); 1.6448 (8.7); 1.6274 (8.7); 1.6041 (0.4); 0.8900 (0.5); 0.8814 (0.8); 0.8732 (0.9); 0.8655 (1.1); 0.8577 (1.0); 0.8494 (0.9); 605.1 0.8438 (0.9); 0.8354 (0.9); 0.8315 (0.9); 0.8277 (0.9); 0.8216 (1.0); 0.8145 (0.9); 0.8054 (0.9); 0.7975 (0.6); 0.7907 (0.5); 0.7807 (0.4); 0.7560 (0.5); 0.7462 (0.9); 0.7362 (0.6); 0.7310 (1.0); 0.7210 (1.4); 0.7165 (0.9); 0.7068 (1.2); 0.6982 (0.6); 0.6854 (0.7); 0.6757 (1.3); 0.6703 (0.9); 0.6666 (1.0); 0.6607 (1.3); 0.6509 (1.0); 0.6412 (0.4); 0.6352 (0.6); −0.0002 (2.6) I-150 [00294] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5369 (2.0); 9.5200 (2.0); 8.3250 (3.6); 8.2501 (16.0); 7.9538 (2.8); 7.3293 (3.0); 7.1907 (7.1); 7.0522 (3.3); 6.1069 (1.4); 6.0898 (2.1); 6.0725 (1.4); 3.3384 (153.0); 3.1712 (0.8); 3.0209 (12.9); 2.7123 (0.4); 2.6770 (0.5); 2.6724 (0.6); 2.6678 (0.5); 2.5623 (0.4); 2.5587 (0.4); 2.5428 (111.1); 2.5305 (0.7); 2.5259 (2.0); 2.5212 (2.8); 2.5125 (37.5); 2.5080 (76.1); 2.5033 (100.6); 2.4987 (73.8); 2.4942 (36.0); 2.3688 (0.4); 2.3348 (0.4); 2.3302 (0.6); 2.3256 (0.4); 1.6534 (8.0); 1.6359 (8.0); 0.9103 (0.4); 0.8967 (0.9); 0.8895 (1.1); 0.8791 (1.6); 0.8748 (1.6); 0.8619 (1.4); 0.8443 (0.6); 0.7846 (0.3); 0.7755 (0.5); 0.7627 (0.6); 0.7357 (2.0); 0.7289 (1.6); 0.7186 (0.9); 0.7085 (0.5); 0.6950 (0.3); −0.0002 (0.6) 497.2 I-151 [00295] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6776 (2.4); 9.6610 (2.5); 8.5211 (8.2); 8.3485 (3.8); 8.3240 (4.5); 8.2661 (12.3); 6.1535 (0.4); 6.1366 (1.6); 6.1194 (2.5); 6.1022 (1.6); 6.0849 (0.4); 3.3334 (221.8); 3.1690 (0.9); 3.0188 (16.0); 2.6811 (0.5); 2.6765 (1.1); 2.6720 (1.6); 2.6673 (1.1); 2.6628 (0.5); 2.5423 (7.4); 2.5255 (5.0); 2.5208 (7.3); 2.5121 (91.5); 2.5076 (185.3); 2.5029 (244.1); 2.4983 (177.1); 2.4937 (84.6); 2.3390 (0.5); 2.3344 (1.1); 2.3297 (1.5); 2.3252 (1.1); 2.3205 (0.5); 2.0755 (5.1); 1.6710 (9.8); 1.6536 (9.8); 0.9086 (0.5); 0.8938 (1.0); 0.8874 (1.0); 0.8819 (1.3); 0.8756 (1.4); 0.8696 (1.8); 0.8657 (1.6); 0.8581 (1.1); 0.8502 (1.2); 0.8332 (0.8); 0.8251 (0.4); 0.8158 (0.4); 0.7815 (0.4); 0.7722 (0.7); 0.7577 (0.8); 0.7474 (1.4); 0.7428 (1.2); 0.7372 (1.7); 0.7332 (1.3); 0.7280 (1.7); 0.7225 (1.2); 0.7177 (1.5); 0.7133 (1.3); 0.7065 (1.3); 0.6968 (0.8); 0.6914 (0.4); 0.6876 (0.4); 0.6819 (0.5); −0.0002 (2.0) 533.2 I-152 [00296] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.2715 (2.4); 9.2546 (2.5); 8.3174 (4.4); 8.2444 (11.9); 7.5631 (5.2); 7.5595 (3.7); 7.5510 (3.1); 7.5483 (3.4); 7.2969 (3.3); 6.0876 (0.4); 6.0700 (1.6); 6.0527 (2.5); 6.0355 (1.6); 6.0182 (0.3); 3.3355 (175.4); 3.1683 (0.9); 3.0193 (16.0); 2.6767 (0.6); 2.6721 (0.9); 2.6675 (0.6); 2.5425 (41.6); 2.5257 (2.9); 2.5209 (4.1); 2.5123 (50.8); 2.5078 (103.0); 2.5031 (135.7); 2.4985 (99.0); 2.4940 (47.8); 2.3346 (0.6); 2.3300 (0.8); 2.3253 (0.6); 2.0843 (0.5); 2.0717 (1.0); 2.0633 (1.1); 2.0593 (0.8); 2.0509 (2.1); 2.0421 (0.8); 2.0383 (1.2); 2.0299 (1.1); 2.0173 (0.6); 1.6375 (9.4); 1.6200 (9.4); 1.0553 (1.2); 1.0441 (3.5); 1.0385 (3.8); 1.0346 (1.8); 1.0281 (1.8); 1.0232 (3.6); 1.0176 (3.6); 1.0073 (1.4); 0.9120 (0.5); 0.8947 (1.0); 0.8827 (1.4); 0.8790 (1.5); 0.8710 (1.8); 0.8656 (1.5); 0.8533 (1.2); 0.8476 (0.9); 0.8351 (0.7); 0.8295 (0.4); 0.8210 (0.4); 0.8089 (1.6); 0.7983 (4.0); 0.7930 (3.9); 0.7859 (3.8); 0.7807 (4.6); 0.7694 (1.8); 521.1 0.7617 (0.5); 0.7553 (0.8); 0.7454 (1.6); 0.7419 (1.3); 0.7366 (1.6); 0.7322 (1.3); 0.7268 (1.4); 0.7207 (1.2); 0.7157 (1.5); 0.7118 (1.3); 0.7058 (1.2); 0.6962 (0.8); 0.6896 (0.4); 0.6853 (0.4); 0.6803 (0.5); −0.0002 (0.8) I-153 [00297] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.7365 (2.6); 9.7199 (2.7); 8.5556 (5.1); 8.5521 (4.3); 8.5137 (5.0); 8.4338 (4.6); 8.3173 (4.8); 8.2698 (9.5); 6.1353 (0.4); 6.1191 (1.6); 6.1019 (2.4); 6.0848 (1.6); 6.0681 (0.4); 3.3341 (318.6); 3.1687 (1.2); 3.0182 (16.0); 2.6716 (1.5); 2.6674 (1.2); 2.5421 (15.6); 2.5068 (173.1); 2.5026 (237.2); 2.4983 (193.4); 2.3332 (1.0); 2.3294 (1.4); 2.3253 (1.2); 1.6629 (9.3); 1.6455 (9.4); 0.9106 (0.6); 0.8959 (1.2); 0.8857 (1.4); 0.8788 (1.8); 0.8708 (2.2); 0.8555 (1.6); 0.8383 (0.8); 0.8205 (0.4); 0.7822 (0.4); 0.7727 (0.7); 0.7590 (0.8); 0.7440 (1.5); 0.7382 (1.9); 0.7305 (2.0); 0.7215 (1.9); 0.7110 (1.3); 0.7006 (0.7); 0.6865 (0.5); −0.0001 (1.2) 563.1 I-154 [00298] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3607 (2.6); 9.3440 (2.7); 8.3185 (4.7); 8.2465 (12.2); 7.9732 (3.7); 7.9694 (6.3); 7.9656 (3.9); 7.6577 (2.2); 7.6524 (5.0); 7.6480 (3.9); 7.6386 (3.8); 7.6354 (4.2); 7.5287 (3.1); 7.3454 (6.7); 7.1621 (3.3); 6.0812 (0.4); 6.0638 (1.7); 6.0467 (2.6); 6.0295 (1.7); 6.0121 (0.4); 3.3354 (306.1); 3.1722 (1.0); 3.0212 (16.0); 2.7116 (0.4); 2.6805 (0.5); 2.6761 (1.2); 2.6715 (1.6); 2.6670 (1.2); 2.6624 (0.6); 2.5419 (113.7); 2.5250 (5.2); 2.5203 (7.8); 2.5116 (97.3); 2.5071 (197.8); 2.5025 (261.8); 2.4979 (192.7); 2.4934 (94.4); 2.3681 (0.4); 2.3385 (0.6); 2.3339 (1.2); 2.3293 (1.7); 2.3248 (1.2); 2.3202 (0.6); 1.6322 (10.0); 1.6148 (10.0); 0.9151 (0.6); 0.8941 (1.7); 0.8849 (2.3); 0.8774 (1.8); 0.8687 (2.0); 0.8511 (0.8); 0.8417 (0.4); 0.8333 (0.4); 0.7872 (0.4); 0.7776 (0.6); 0.7654 (0.8); 0.7494 (2.0); 0.7402 (3.2); 0.7322 (2.0); 0.7239 (1.2); 0.7140 (0.7); 0.7047 (0.4); 0.7002 (0.4); −0.0003 (1.7) 543.1 I-155 [00299] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4386 (2.5); 9.4219 (2.6); 8.3172 (4.7); 8.2533 (12.4); 8.0200 (3.7); 8.0159 (5.7); 8.0119 (4.0); 7.8063 (3.8); 7.8038 (3.5); 7.8016 (3.4); 7.7991 (3.5); 7.7961 (4.0); 7.7934 (3.8); 7.7909 (2.6); 6.0906 (0.3); 6.0736 (1.7); 6.0565 (2.6); 6.0394 (1.7); 6.0216 (0.4); 3.3358 (176.8); 3.1711 (1.0); 3.0199 (16.0); 2.6813 (0.3); 2.6768 (0.8); 2.6722 (1.0); 2.6676 (0.8); 2.6630 (0.4); 2.5425 (14.2); 2.5258 (3.4); 2.5211 (4.8); 2.5124 (60.9); 2.5078 (124.2); 2.5032 (164.1); 2.4986 (119.8); 2.4940 (57.8); 2.3346 (0.7); 2.3300 (1.0); 2.3254 (0.7); 1.6406 (10.0); 1.6232 (10.1); 0.9121 (0.5); 0.8975 (1.1); 0.8874 (1.3); 0.8812 (1.8); 0.8777 (1.7); 0.8737 (2.0); 0.8645 (1.2); 0.8591 (1.4); 0.8417 (0.8); 0.8329 (0.4); 0.8247 (0.4); 0.7838 (0.4); 0.7743 (0.7); 0.7603 (0.8); 0.7498 (1.5); 0.7455 (1.4); 0.7403 (1.6); 0.7341 (1.9); 0.7241 (1.8); 515.2 0.7138 (1.2); 0.7041 (0.8); 0.6987 (0.4); 0.6947 (0.4); 0.6892 (0.5); −0.0002(1.2) I-156 [00300] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6264 (2.6); 9.6093 (2.7); 8.5053 (9.1); 8.3363 (4.0); 8.3130 (1.2); 8.1817 (3.3); 8.1105 (16.0); 6.0895 (0.4); 6.0718 (1.9); 6.0546 (3.0); 6.0373 (2.0); 6.0197 (0.4); 3.7030 (0.5); 3.6624 (0.3); 3.6294 (0.4); 3.3478 (366.1); 3.2496 (3.6); 3.1031 (0.8); 3.0250 (2.0); 2.6907 (0.7); 2.6818 (1.1); 2.6773 (2.2); 2.6728 (3.1); 2.6682 (2.2); 2.6637 (1.1); 2.5263 (10.2); 2.5216 (15.0); 2.5129 (176.8); 2.5084 (356.4); 2.5038 (467.0); 2.4992 (337.3); 2.4946 (162.0); 2.3397 (1.0); 2.3352 (2.2); 2.3306 (3.0); 2.3260 (2.2); 2.3216 (1.0); 2.1367 (0.3); 2.0904 (0.6); 2.0783 (1.3); 2.0740 (1.0); 2.0696 (1.3); 2.0665 (1.0); 2.0575 (2.5); 2.0453 (1.4); 2.0367 (1.3); 2.0246 (0.7); 1.6260 (10.2); 1.6085 (10.1); 1.3422 (0.7); 1.0509 (0.6); 1.0426 (0.5); 1.0322 (0.7); 1.0154 (2.0); 1.0110 (3.3); 1.0079 (3.6); 0.9943 (1.9); 0.9901 (3.1); 0.9870 (3.7); 0.9680 (0.5); 0.9575 (0.4); 0.9010 (0.4); 0.8967 (0.5); 0.8897 (0.6); 0.8848 (0.6); 0.8744 (2.0); 0.8675 (1.4); 0.8620 (2.2); 0.8555 (2.3); 0.8485 (1.8); 0.8363 (1.6); 547.3 0.8256 (0.5); 0.8213 (0.7); 0.8136 (0.4); 0.8090 (0.3); 0.1460 (1.3); 0.0081 (10.2); −0.0001 (322.4); −0.0084 (10.1); −0.0200 (0.4); −0.1495 (1.3) I-157 [00301] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.2291 (2.7); 9.2120 (2.8); 8.1076 (16.0); 7.5400 (6.2); 7.5361 (5.7); 7.5318 (3.9); 7.5289 (4.0); 7.5264 (3.4); 7.2934 (3.8); 6.0197 (0.4); 6.0026 (2.0); 5.9852 (3.2); 5.9679 (2.0); 5.9504 (0.4); 3.3338 (82.9); 3.2389 (2.0); 3.1456 (0.4); 3.1044 (0.4); 3.0265 (2.0); 2.6780 (0.4); 2.6734 (0.6); 2.6689 (0.4); 2.5269 (2.0); 2.5222 (3.0); 2.5135 (35.2); 2.5090 (70.1); 2.5044 (91.4); 2.4998 (66.6); 2.4952 (32.1); 2.3357 (0.4); 2.3313 (0.6); 2.3267 (0.4); 2.0848 (1.0); 2.0726 (2.1); 2.0640 (2.4); 2.0519 (4.2); 2.0401 (2.4); 2.0312 (2.2); 2.0191 (1.0); 1.5934 (10.6); 1.5759 (10.5); 1.0582 (1.0); 1.0469 (4.0); 1.0413 (4.4); 1.0305 (1.8); 1.0260 (4.2); 1.0203 (4.4); 1.0093 (4.2); 1.0039 (4.2); 0.9881 (3.1); 0.9830 (4.3); 0.9605 (0.4); 0.9557 (0.4); 0.8964 (0.5); 0.8927 (0.6); 0.8851 (0.7); 0.8805 (0.7); 0.8679 (2.2); 0.8636 (1.5); 0.8560 (2.2); 0.8513 (1.6); 0.8451 (1.5); 0.8403 (2.0); 0.8331 (1.6); 0.8281 (1.9); 0.8119 (2.3); 0.8019 (4.1); 0.7987 (4.0); 0.7960 (3.7); 0.7894 (3.8); 0.7855 (3.7); 0.7737 (1.4); 0.0080 (1.5); −0.0002 (44.4); −0.0086 (1.3) 535.4 I-158 [00302] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6840 (1.3); 9.6677 (1.4); 8.6405 (0.6); 8.6338 (6.8); 8.4926 (1.7); 8.4882 (2.9); 8.4840 (2.1); 8.3987 (3.0); 8.3294 (0.3); 8.2100 (1.7); 8.2054 (2.8); 8.2010 (1.6); 7.5558 (1.0); 7.4262 (2.2); 7.2963 (1.2); 6.0543 (1.0); 6.0375 (1.4); 6.0203 (0.9); 3.9429 (0.8); 3.5238 (0.4); 3.5023 (0.5); 3.4661 (0.7); 3.3575 (221.2); 3.3413 (1100.6); 2.7641 (0.4); 2.7152 (0.5); 2.6839 (2.2); 2.6793 (4.8); 2.6747 (6.8); 2.6701 (4.8); 2.6656 (2.3); 2.6145 (0.4); 2.5916 (0.5); 2.5451 (116.9); 2.5282 (22.0); 2.5236 (32.8); 2.5148 (406.1); 2.5104 (819.8); 2.5058 (1071.8); 2.5011 (771.7); 2.4966 (368.9); 2.3713 (0.6); 2.3536 (16.0); 2.3417 (2.4); 2.3372 (4.8); 2.3325 (6.6); 2.3280 (4.8); 2.3235 (2.2); 2.0780 (1.1); 1.8630 (0.4); 1.6265 (5.2); 1.6090 (5.0) 487.0 I-159 [00303] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6399 (1.4); 9.6232 (1.4); 8.6404 (7.1); 8.4900 (1.8); 8.4864 (3.3); 8.4829 (1.8); 8.1675 (1.9); 8.1652 (1.8); 8.1061 (1.9); 6.0683 (0.9); 6.0512 (1.4); 6.0340 (1.0); 3.4030 (1.0); 3.3694 (21.8); 3.3446 (317.6); 2.6841 (0.5); 2.6794 (1.2); 2.6748 (1.6); 2.6702 (1.1); 2.6656 (0.5); 2.5451 (25.7); 2.5283 (5.0); 2.5236 (7.5); 2.5150 (97.0); 2.5104 (196.6); 2.5058 (256.5); 2.5012 (182.4); 2.4966 (85.6); 2.3535 (16.0); 2.3420 (0.7); 2.3373 (1.2); 2.3326 (1.6); 2.3280 (1.2); 2.3235 (0.6); 1.6342 (5.3); 1.6168 (5.2) 501.0 I-160 [00304] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.7306 (1.6); 9.7148 (1.5); 8.6326 (6.5); 8.6187 (0.4); 8.6054 (0.3); 8.5682 (3.2); 8.5643 (2.1); 8.5168 (2.8); 8.4372 (2.6); 6.0617 (1.0); 6.0450 (1.5); 6.0277 (1.0); 3.5830 (0.4); 3.5415 (0.5); 3.3475 (1006.5); 3.3421 (1430.1); 3.2484 (0.6); 2.7143 (0.4); 2.6834 (3.0); 2.6792 (6.3); 2.6746 (8.7); 2.6701 (6.2); 2.6657 (2.8); 2.6353 (0.4); 2.5450 (80.9); 2.5281 (28.8); 2.5233 (43.4); 2.5147 (542.7); 2.5102 (1075.9); 2.5057 (1390.5); 2.5011 (995.9); 2.4966 (472.8); 2.3715 (0.6); 2.3549 (16.0); 2.3415 (3.1); 2.3370 (6.4); 2.3325 (8.6); 2.3279 (6.1); 2.3235 (2.8); 2.2484 (0.4); 2.2320 (0.4); 2.0779 (1.7); 1.8758 (0.6); 1.8625 (0.5); 1.6317 (5.8); 1.6143 (5.7); 1.2385 (0.4); 1.1303 (0.4); 1.1122 (0.4) 505.0 I-161 [00305] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.7712 (1.3); 9.7543 (1.3); 8.6336 (6.9); 8.5314 (3.0); 8.3953 (1.8); 8.3024 (0.3); 8.1463 (1.8); 7.5846 (0.9); 7.4545 (2.1); 7.3245 (1.1); 6.0705 (1.0); 6.0535 (1.4); 6.0358 (0.9); 3.5277 (0.3); 3.5108 (0.4); 3.3395 (952.8); 2.7145 (0.4); 2.6839 (2.6); 2.6793 (5.5); 2.6748 (7.6); 2.6701 (5.5); 2.6656 (2.5); 2.5451 (104.0); 2.5283 (25.2); 2.5236 (36.7); 2.5149 (463.9); 2.5104 (935.2); 2.5058 (1217.4); 2.5011 (864.0); 2.4966 (404.2); 2.3717 (0.5); 2.3554 (16.0); 2.3417 (2.6); 2.3372 (5.5); 2.3326 (7.5); 2.3280 (5.4); 2.3235 (2.4); 2.2527 (0.4); 2.2364 (0.4); 2.0783 (1.4); 1.8785 (0.5); 1.8650 (0.6); 1.6378 (5.2); 1.6203 (5.2); 0.0034 (0.4) 537.0 I-162 [00306] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 10.0912 (1.5); 10.0742 (1.5); 9.1284 (5.8); 9.1243 (6.0); 8.9038 (0.5); 8.8993 (0.6); 8.8461 (0.4); 8.7840 (0.4); 8.6798 (2.5); 8.6351 (7.4); 8.5397 (0.4); 6.1363 (0.9); 6.1186 (1.5); 6.1016 (1.0); 4.0046 (1.5); 3.5478 (0.3); 3.5325 (0.3); 3.4924 (0.4); 3.4555 (0.6); 3.3429 (665.7); 3.3373 (952.6); 2.7151 (0.4); 2.6839 (2.5); 2.6794 (5.3); 2.6748 (7.5); 2.6702 (5.4); 2.6657 (2.5); 2.6356 (0.4); 2.6272 (0.3); 2.5451 (76.3); 2.5283 (24.2); 2.5236 (37.2); 2.5149 (455.0); 2.5104 (918.4); 2.5058 (1201.5); 2.5012 (865.6); 2.4967 (415.9); 2.3634 (16.0); 2.3416 (2.5); 2.3372 (5.3); 2.3326 (7.4); 2.3281 (5.3); 2.3238 (2.4); 2.0785 (1.6); 1.8952 (0.3); 1.6653 (5.4); 1.6479 (5.4); 1.2367 (0.5); 1.1308 (0.6); 1.1138 (0.6) 603.0 I-163 [00307] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5791 (1.4); 9.5618 (1.4); 8.6424 (7.1); 8.3279 (1.8); 8.3242 (3.4); 8.3205 (2.2); 8.2820 (2.2); 8.2774 (3.1); 8.2734 (1.8); 8.2491 (0.4); 8.1512 (2.0); 8.1466 (3.2); 8.1424 (1.8); 6.0528 (1.1); 6.0358 (1.5); 6.0184 (1.0); 3.6241 (0.3); 3.6068 (0.3); 3.5104 (0.5); 3.5045 (0.5); 3.3376 (1124.0); 3.0610 (0.4); 3.0487 (0.7); 3.0410 (0.7); 3.0294 (1.2); 3.0175 (0.6); 3.0103 (0.5); 2.9978 (0.4); 2.7145 (0.5); 2.6837 (3.2); 2.6793 (6.8); 2.6747 (9.4); 2.6701 (6.8); 2.6656 (3.1); 2.5451 (106.7); 2.5283 (29.9); 2.5236 (43.4); 2.5149 (569.1); 2.5104 (1150.3); 2.5058 (1503.0); 2.5011 (1080.2); 2.4966 (516.5); 2.3710 (0.6); 2.3539 (16.0); 2.3419 (3.6); 2.3371 (6.7); 2.3325 (9.2); 2.3280 (6.6); 2.3234 (3.0); 2.2436 (0.6); 2.2280 (0.6); 477.0 2.0784 (1.6); 1.6247 (5.3); 1.6073 (5.2); 1.2404 (0.4); 1.1969 (1.7); 1.1891 (1.8); 1.1796 (1.1); 1.1598 (0.4); 1.1483 (0.4); 1.1234 (0.6); 1.1111 (1.6); 1.1040 (1.5); 1.0914 (1.6); 1.0855 (1.3) I-164 [00308] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6595 (1.4); 9.6426 (1.5); 8.6422 (7.5); 8.4614 (1.8); 8.4579 (3.3); 8.4545 (2.0); 8.1827 (2.0); 8.0833 (2.0); 6.0695 (1.0); 6.0524 (1.5); 6.0353 (1.0); 3.3378 (620.1); 3.0670 (0.6); 3.0591 (0.7); 3.0475 (1.3); 3.0354 (0.7); 3.0281 (0.7); 3.0156 (0.4); 2.6838 (1.4); 2.6793 (3.0); 2.6747 (4.2); 2.6702 (3.0); 2.6656 (1.4); 2.5452 (30.1); 2.5282 (13.0); 2.5235 (19.1); 2.5148 (248.5); 2.5104 (501.9); 2.5058 (656.4); 2.5012 (471.9); 2.4966 (225.8); 2.3555 (16.0); 2.3420 (1.7); 2.3371 (3.1); 2.3326 (4.1); 2.3280 (2.9); 2.3236 (1.3); 2.0787 (0.5); 1.6366 (5.4); 1.6192 (5.4); 1.2405 (0.4); 1.2279 (0.8); 1.2187 (1.7); 1.2080 (1.8); 1.1984 (1.2); 1.1770 (0.4); 1.1381 (0.5); 1.1251 (1.8); 1.1186 (1.5); 1.1062 (1.6); 1.1000 (1.2) 527.1 I-165 [00309] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.7187 (1.4); 9.7020 (1.4); 8.6910 (2.6); 8.6455 (7.9); 8.5629 (2.2); 8.4277 (2.3); 6.0929 (0.9); 6.0758 (1.5); 6.0586 (1.0); 3.4300 (0.6); 3.3938 (15.8); 3.3378 (221.5); 2.6840 (0.6); 2.6794 (1.2); 2.6748 (1.6); 2.6702 (1.2); 2.6658 (0.5); 2.5451 (24.5); 2.5283 (5.3); 2.5236 (7.8); 2.5149 (98.3); 2.5104 (197.3); 2.5058 (256.6); 2.5012 (183.2); 2.4966 (86.5); 2.3547 (16.0); 2.3418 (0.7); 2.3373 (1.2); 2.3326 (1.6); 2.3280 (1.2); 2.3236 (0.5); 2.0785 (0.3); 1.6438 (5.2); 1.6264 (5.2) 485.1 I-166 [00310] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4570 (2.1); 9.4389 (2.2); 8.6794 (16.0); 8.3558 (0.3); 8.3470 (10.6); 8.3156 (0.5); 8.3076 (4.3); 8.3059 (4.4); 8.1694 (4.6); 8.1673 (4.4); 6.0890 (0.4); 6.0717 (1.6); 6.0541 (2.6); 6.0365 (1.7); 6.0190 (0.3); 5.7558 (7.8); 4.0822 (0.4); 3.3595 (0.4); 3.3320 (171.2); 3.3092 (0.4); 2.6771 (0.6); 2.6725 (0.8); 2.6680 (0.6); 2.5261 (2.8); 2.5213 (4.1); 2.5127 (47.2); 2.5082 (95.3); 2.5035 (125.0); 2.4989 (90.3); 2.4943 (43.3); 2.3350 (0.6); 2.3304 (0.8); 2.3257 (0.6); 1.6584 (9.6); 1.6410 (9.6); 0.1459 (0.5); 0.0080 (4.4); −0.0002 (129.7); −0.0086 (4.2); −0.1497 (0.5) 428.0 I-167 [00311] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 11.5592 (0.3); 9.3204 (2.6); 9.3023 (2.5); 8.6776 (14.9); 8.3428 (11.4); 8.3155 (5.9); 8.1353 (0.4); 8.0731 (7.2); 8.0687 (7.8); 7.9904 (8.1); 7.9861 (7.8); 7.4472 (0.8); 7.4334 (0.5); 7.4111 (0.4); 6.0610 (0.5); 6.0433 (2.0); 6.0256 (2.8); 6.0078 (1.8); 5.9904 (0.5); 5.7553 (2.4); 4.4930 (0.8); 4.4718 (1.0); 4.4536 (0.8); 4.0342 (0.9); 3.9204 (0.8); 3.9067 (0.9); 3.8989 (0.8); 3.8840 (1.1); 3.7602 (0.6); 3.7433 (0.6); 3.7223 (0.9); 3.7012 (0.8); 3.6827 (13.2); 3.6617 (0.6); 3.6264 (0.4); 3.5590 (0.4); 3.5081 (0.4); 3.4524 (0.7); 3.3298 (2562.0); 3.2449 (0.7); 3.1654 (0.3); 2.8008 (0.3); 2.7477 (0.3); 2.7146 (0.4); 2.6802 (5.2); 2.6757 (11.4); 2.6711 (16.0); 2.6666 (11.9); 2.6622 (5.6); 2.6401 (0.6); 2.6276 (0.7); 2.6063 394.0 (1.0); 2.5840 (1.7); 2.5247 (51.6); 2.5200 (75.6); 2.5112 (926.5); 2.5067 (1902.9); 2.5022 (2518.1); 2.4976 (1843.6); 2.4931 (899.6); 2.4338 (1.3); 2.3990 (0.8); 2.3596 (0.4); 2.3381 (5.2); 2.3335 (11.1); 2.3290 (15.8); 2.3245 (11.5); 2.3200 (5.3); 2.2940 (0.4); 1.9182 (0.6); 1.9044 (0.6); 1.8864 (0.6); 1.8041 (0.4); 1.6388 (10.8); 1.6215 (11.0); 1.4898 (0.5); 1.4722 (0.6); 1.3478 (0.3); 1.2350 (1.2); 1.2159 (0.5); 1.1523 (0.4); 1.1307 (0.4); 1.1054 (0.4); 0.8527 (0.4); 0.1459 (9.2); 0.0194 (2.1); 0.0080 (72.1); −0.0002 (2284.9); −0.0086 (74.3); −0.0145 (6.4); −0.0240 (2.1); −0.0327 (1.3); −0.0453 (0.9); −0.0774 (0.5); −0.0921 (0.4); −0.1414 (0.5); −0.1497 (9.3); −0.7968 (0.3); −2.8850 (0.4) I-168 [00312] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.7518 (2.6); 9.7354 (2.6); 8.6649 (16.0); 8.3423 (11.9); 8.3151 (2.9); 8.2640 (6.4); 8.2615 (6.8); 8.2124 (6.4); 6.0863 (0.4); 6.0688 (1.8); 6.0518 (2.8); 6.0348 (1.8); 6.0175 (0.4); 3.4060 (0.4); 3.3878 (0.5); 3.3271 (1191.3); 2.6898 (1.6); 2.6801 (2.4); 2.6757 (5.1); 2.6711 (6.9); 2.6666 (5.0); 2.6620 (2.4); 2.5246 (27.2); 2.5198 (41.5); 2.5112 (421.7); 2.5067 (833.6); 2.5021 (1082.3); 2.4975 (779.2); 2.4930 (373.6); 2.3380 (2.2); 2.3335 (4.9); 2.3290 (6.7); 2.3244 (4.9); 2.3200 (2.2); 1.6452 (11.0); 1.6279 (10.9); 1.2553 (0.4); 0.1459 (3.6); 0.0079 (31.4); −0.0002 (859.9); −0.0086 (27.6); −0.0278 (0.5); −0.0395 (0.3); −0.1497 (3.7) 428.0 I-169 [00313] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3822 (2.8); 9.3655 (2.9); 8.6131 (16.0); 7.8218 (3.5); 7.8180 (6.1); 7.8142 (3.9); 7.7366 (3.5); 7.7341 (4.0); 7.7316 (3.6); 7.4875 (4.0); 6.0060 (0.4); 5.9890 (2.0); 5.9719 (3.1); 5.9547 (2.0); 5.9376 (0.4); 3.3321 (124.9); 2.6776 (0.5); 2.6731 (0.7); 2.6686 (0.5); 2.5267 (2.1); 2.5220 (3.1); 2.5132 (37.5); 2.5088 (76.5); 2.5042 (101.0); 2.4996 (73.7); 2.4951 (35.9); 2.3356 (0.4); 2.3310 (0.6); 2.3264 (0.4); 2.1113 (0.6); 2.0992 (1.2); 2.0904 (1.3); 2.0875 (1.1); 2.0785 (2.6); 2.0664 (1.5); 2.0578 (1.4); 2.0456 (0.7); 1.8631 (2.0); 1.8517 (5.2); 1.8439 (6.3); 1.8329 (2.7); 1.7925 (0.4); 1.7095 (0.3); 1.6700 (3.2); 1.6579 (6.1); 1.6503 (5.5); 1.6379 (2.5); 1.5996 (10.7); 1.5821 (10.6); 1.2343 (0.4); 1.2250 (0.4); 1.2174 (0.4); 1.2078 (0.4); 1.0560 (0.3); 1.0362 (3.4); 1.0315 (4.4); 1.0155 (3.3); 1.0107 (4.5); 0.9929 (0.5); 514.0 0.9830 (0.3); 0.9125 (0.4); 0.9089 (0.6); 0.9009 (0.6); 0.8964 (0.6); 0.8854 (2.5); 0.8792 (1.5); 0.8731 (2.8); 0.8675 (2.4); 0.8607 (2.2); 0.8562 (1.5); 0.8487 (2.0); 0.8371 (0.5); 0.8328 (0.7); 0.8250 (0.4); 0.8216 (0.4); 0.1459 (0.4); 0.0080 (2.9); −0.0002 (88.5); −0.0085 (3.0); −0.1496 (0.4) I-170 [00314] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.7752 (3.0); 9.7586 (3.1); 8.7894 (0.9); 8.7783 (2.4); 8.7665 (2.4); 8.7560 (0.8); 8.5226 (4.1); 8.5191 (7.0); 8.5156 (4.0); 8.3754 (4.4); 8.3150 (1.9); 8.2639 (14.3); 8.2420 (16.0); 8.1343 (4.4); 7.5764 (2.4); 7.4466 (5.6); 7.3168 (2.9); 6.1242 (0.4); 6.1064 (2.0); 6.0893 (3.0); 6.0724 (2.0); 6.0551 (0.4); 3.9546 (0.3); 3.7744 (0.4); 3.6666 (0.3); 3.3899 (0.9); 3.3320 (1174.0); 2.8065 (14.8); 2.7950 (14.6); 2.6806 (1.6); 2.6762 (3.4); 2.6716 (4.7); 2.6671 (3.5); 2.6626 (1.6); 2.5251 (17.7); 2.5203 (26.8); 2.5117 (290.7); 2.5072 (573.5); 2.5027 (743.0); 2.4981 (538.0); 2.4936 (260.8); 2.3387 (1.5); 2.3341 (3.3); 2.3295 (4.6); 2.3250 (3.2); 2.3205 (1.5); 2.0744 (1.3); 1.6543 (11.6); 1.6368 (11.6); 0.1459 (1.6); 0.0080 (13.0); −0.0002 (387.8); −0.0085 (13.7); −0.1495 (1.6) 555.0 I-171 [00315] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.7855 (2.7); 9.7689 (2.8); 8.5305 (3.6); 8.5271 (6.4); 8.5235 (3.8); 8.3890 (4.0); 8.3159 (0.5); 8.2759 (0.4); 8.2674 (12.4); 8.1586 (16.0); 8.1376 (4.0); 7.5802 (2.2); 7.4504 (5.2); 7.3206 (2.7); 6.1370 (0.4); 6.1199 (1.8); 6.1029 (2.8); 6.0857 (1.9); 6.0686 (0.4); 3.3320 (284.5); 3.2462 (2.4); 3.1590 (0.4); 3.0861 (0.6); 3.0278 (2.4); 2.6769 (1.0); 2.6724 (1.3); 2.6678 (1.0); 2.6634 (0.4); 2.5259 (4.4); 2.5211 (6.7); 2.5124 (79.8); 2.5080 (160.4); 2.5034 (208.9); 2.4988 (150.5); 2.4943 (72.2); 2.3392 (0.4); 2.3348 (1.0); 2.3302 (1.3); 2.3257 (1.0); 1.9895 (1.3); 1.6654 (10.8); 1.6480 (10.8); 1.1935 (0.4); 1.1757 (0.7); 1.1579 (0.4); 0.1459 (0.5); 0.0080 (4.2); −0.0002 (127.8); −0.0085 (4.1); −0.1496 (0.5) 569.3 I-172 [00316] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.2219 (2.4); 9.2047 (2.4); 8.3164 (0.4); 8.2658 (4.8); 7.5385 (5.3); 7.5347 (5.1); 7.5309 (3.6); 7.5279 (3.5); 7.2928 (3.3); 6.0263 (0.4); 6.0095 (1.6); 5.9922 (2.5); 5.9749 (1.6); 5.9577 (0.3); 3.3296 (132.6); 3.1533 (1.1); 3.0126 (16.0); 2.6764 (1.0); 2.6720 (1.3); 2.6675 (1.0); 2.5251 (7.1); 2.5119 (85.1); 2.5075 (158.8); 2.5030 (201.9); 2.4985 (147.8); 2.4941 (73.8); 2.3343 (0.9); 2.3298 (1.3); 2.3253 (0.9); 2.0836 (0.8); 2.0750 (1.9); 2.0726 (1.7); 2.0618 (2.0); 2.0517 (2.9); 2.0402 (2.0); 2.0312 (1.6); 2.0191 (0.8); 1.5960 (8.6); 1.5785 (8.4); 1.1694 (0.5); 1.0564 (1.1); 1.0455 (3.4); 1.0399 (3.7); 1.0294 (1.9); 1.0246 (3.6); 1.0189 (3.9); 1.0092 (4.0); 1.0043 (3.8); 0.9886 (2.8); 0.9833 (3.7); 0.9627 (0.4); 0.9560 (0.3); 0.9236 (0.3); 0.9070 (0.7); 0.8926 (1.6); 0.8848 (1.8); 0.8807 (2.1); 0.8687 (4.0); 0.8571 (3.4); 0.8519 (2.7); 0.8484 (2.8); 0.8429 (2.6); 0.8313 (2.2); 0.8089 (1.9); 0.7985 (3.8); 0.7934 (3.6); 0.7862 (3.6); 0.7813 (3.6); 0.7701 (1.5); 0.7635 (0.9); 0.7487 (0.9); 561.3 0.7383 (1.6); 0.7341 (1.5); 0.7286 (1.7); 0.7246 (1.5); 0.7198 (1.8); 0.7143 (1.5); 0.7098 (1.7); 0.7055 (1.4); 0.6992 (1.3); 0.6892 (0.8); 0.6741 (0.5); 0.1460 (0.5); 0.0079 (5.6); −0.0002 (103.9); −0.0084 (4.4); −0.1496 (0.5) I-173 [00317] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.2316 (0.6); 9.2143 (3.4); 9.1971 (3.0); 8.7430 (0.8); 8.7322 (2.4); 8.7208 (2.3); 8.7093 (0.7); 8.3163 (0.6); 8.2523 (0.6); 8.1905 (16.0); 7.5331 (1.5); 7.5229 (7.5); 7.5194 (7.8); 7.5140 (4.7); 7.2905 (4.5); 5.9981 (0.8); 5.9812 (2.6); 5.9641 (3.6); 5.9468 (2.1); 5.9294 (0.4); 3.3305 (168.1); 2.7989 (14.1); 2.7874 (14.0); 2.6813 (0.6); 2.6766 (1.2); 2.6721 (1.7); 2.6675 (1.2); 2.6629 (0.6); 2.5256 (5.6); 2.5209 (8.1); 2.5122 (97.7); 2.5077 (197.7); 2.5031 (258.6); 2.4985 (184.8); 2.4940 (87.6); 2.3391 (0.5); 2.3346 (1.2); 2.3300 (1.6); 2.3254 (1.1); 2.3209 (0.5); 2.0811 (1.2); 2.0690 (2.7); 2.0602 (3.0); 2.0482 (5.1); 2.0362 (2.9); 2.0274 (2.6); 2.0151 (1.2); 1.5825 (11.3); 1.5650 (11.1); 1.0554 (1.6); 1.0443 (4.6); 1.0387 (5.1); 1.0347 (2.5); 1.0282 (2.6); 1.0233 (4.9); 1.0177 (5.4); 1.0080 (5.6); 1.0029 (4.8); 0.9877 (4.0); 0.9821 (4.9); 0.9695 (0.4); 0.9624 (0.5); 0.9551 (0.4); 0.8898 (0.8); 0.8818 (0.8); 0.8776 (0.8); 0.8655 (2.8); 0.8604 (1.8); 0.8534 (2.9); 0.8478 (1.9); 0.8452 (2.0); 521.2 0.8397 (2.4); 0.8329 (1.8); 0.8275 (2.3); 0.8077 (2.4); 0.7971 (5.6); 0.7917 (5.0); 0.7847 (5.1); 0.7796 (5.0); 0.7682 (1.5); 0.1459 (0.6); 0.0080 (5.0); −0.0002 (160.1); −0.0086 (5.0); −0.1497 (0.6) I-174 [00318] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5526 (2.5); 9.5362 (2.5); 9.0522 (6.0); 9.0479 (5.9); 8.8600 (3.4); 8.8538 (3.4); 8.6710 (16.0); 8.3292 (12.1); 8.3159 (0.7); 8.2424 (2.9); 8.2403 (3.4); 8.2380 (2.9); 6.0835 (0.4); 6.0662 (1.8); 6.0491 (2.8); 6.0321 (1.8); 6.0146 (0.4); 3.3316 (365.5); 2.6809 (0.6); 2.6764 (1.3); 2.6719 (1.8); 2.6673 (1.3); 2.6628 (0.6); 2.5254 (5.8); 2.5207 (8.4); 2.5120 (103.7); 2.5075 (208.5); 2.5029 (272.6); 2.4983 (195.6); 2.4938 (92.8); 2.3389 (0.6); 2.3343 (1.2); 2.3298 (1.7); 2.3252 (1.2); 2.3206 (0.6); 2.0750 (3.6); 1.6438 (11.0); 1.6263 (11.0); 0.1460 (0.7); 0.0081 (4.8); −0.0001 (162.1); −0.0084 (5.2); −0.1495 (0.7) 410.1 I-175 [00319] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5306 (1.3); 9.5140 (1.3); 9.0626 (3.0); 9.0583 (3.0); 8.8600 (1.8); 8.8537 (1.8); 8.6353 (7.7); 8.3158 (0.3); 8.2535 (1.8); 6.0458 (1.0); 6.0288 (1.6); 6.0117 (1.0); 3.3303 (160.9); 2.6762 (0.7); 2.6716 (1.0); 2.6671 (0.7); 2.6625 (0.4); 2.5251 (3.2); 2.5203 (4.8); 2.5116 (58.4); 2.5072 (117.2); 2.5026 (153.0); 2.4980 (110.7); 2.4935 (53.6); 2.3503 (16.0); 2.3389 (0.6); 2.3340 (0.8); 2.3296 (1.2); 2.3249 (0.7); 2.3204 (0.4); 1.6230 (5.6); 1.6056 (5.5); 0.1458 (0.3); 0.0079 (2.6); −0.0002 (78.5); −0.0086 (2.4); −0.1497 (0.3) 424.2 I-176 [00320] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.2271 (0.5); 9.2029 (3.4); 9.1859 (3.5); 8.7553 (3.7); 8.7458 (3.7); 8.3166 (0.6); 8.1838 (16.0); 8.1064 (2.4); 7.5388 (0.9); 7.5348 (0.9); 7.5147 (8.3); 7.5112 (8.5); 7.5059 (5.2); 7.2885 (5.1); 5.9886 (0.6); 5.9837 (0.7); 5.9715 (2.4); 5.9542 (3.6); 5.9370 (2.3); 5.9197 (0.4); 3.3316 (253.4); 2.8301 (0.4); 2.8204 (1.2); 2.8112 (1.7); 2.8024 (2.6); 2.7929 (2.6); 2.7840 (1.7); 2.7748 (1.2); 2.7651 (0.4); 2.6818 (0.5); 2.6771 (1.2); 2.6725 (1.6); 2.6680 (1.1); 2.6634 (0.5); 2.5260 (5.4); 2.5213 (7.8); 2.5126 (89.9); 2.5081 (180.2); 2.5035 (233.3); 2.4989 (165.9); 2.4943 (77.6); 2.3396 (0.5); 2.3350 (1.0); 2.3304 (1.5); 2.3257 (1.0); 2.3212 (0.5); 2.0802 (1.1); 2.0757 (0.7); 2.0694 (2.2); 2.0670 (2.2); 2.0582 (3.0); 2.0488 (4.4); 2.0462 (4.1); 2.0369 (3.1); 2.0334 (2.4); 2.0281 (2.4); 2.0254 (2.0); 2.0158 (1.1); 2.0126 (1.0); 1.5923 (1.9); 1.5769 (13.6); 1.5595 (12.6); 1.0541 (1.9); 1.0428 (5.4); 1.0373 (5.9); 1.0333 (3.0); 1.0267 (3.4); 1.0219 (5.8); 1.0162 (6.2); 1.0095 (5.4); 1.0043 (6.9); 0.9888 (4.6); 0.9832 (6.4); 0.9644 (0.6); 0.9566 (0.5); 0.8907 547.2 (0.8); 0.8820 (0.9); 0.8784 (0.9); 0.8664 (3.6); 0.8610 (2.0); 0.8542 (3.7); 0.8480 (2.6); 0.8415 (3.0); 0.8350 (2.0); 0.8294 (2.9); 0.8118 (1.4); 0.8044 (3.0); 0.7939 (6.2); 0.7887 (6.2); 0.7816 (5.7); 0.7764 (6.2); 0.7649 (1.9); 0.7550 (1.6); 0.7417 (4.0); 0.7370 (5.7); 0.7248 (5.4); 0.7188 (4.4); 0.7073 (1.8); 0.5925 (2.0); 0.5819 (5.6); 0.5757 (5.1); 0.5717 (4.7); 0.5663 (4.4); 0.5539 (1.4); 0.1460 (0.5); 0.0081 (4.6); −0.0001 (147.1); −0.0085 (4.3); −0.1495 (0.5) I-177 [00321] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5839 (3.1); 9.5670 (3.2); 8.7438 (0.8); 8.7326 (2.5); 8.7211 (2.5); 8.7097 (0.8); 8.4540 (4.2); 8.4504 (7.6); 8.4468 (4.2); 8.1944 (16.0); 8.1283 (4.3); 8.1260 (4.2); 8.0969 (4.4); 6.0611 (0.5); 6.0437 (2.2); 6.0265 (3.4); 6.0093 (2.2); 5.9922 (0.4); 3.3644 (36.0); 3.3319 (362.0); 2.7966 (14.4); 2.7851 (14.2); 2.6808 (0.5); 2.6762 (1.0); 2.6716 (1.4); 2.6670 (1.0); 2.6627 (0.5); 2.5251 (4.0); 2.5203 (5.9); 2.5117 (82.1); 2.5072 (168.8); 2.5027 (223.5); 2.4981 (159.8); 2.4936 (75.0); 2.3386 (0.4); 2.3340 (1.0); 2.3295 (1.4); 2.3249 (1.0); 2.0905 (0.6); 2.0783 (1.4); 2.0696 (1.4); 2.0576 (2.8); 2.0455 (1.6); 2.0369 (1.5); 2.0246 (0.7); 1.6100 (11.4); 1.5926 (11.3); 1.0310 (0.6); 1.0138 (4.2); 1.0099 (4.7); 0.9932 (4.2); 0.9889 (4.4); 0.9743 (0.7); 0.9615 (0.4); 0.8975 (0.5); 0.8848 (0.6); 0.8778 (1.7); 0.8730 (2.1); 0.8603 (3.5); 0.8558 (3.1); 0.8522 (2.6); 0.8478 (1.7); 0.8409 (1.5); 0.8286 (0.6); 0.8204 (0.4); 0.0080 (1.2); −0.0001 (41.3); −0.0085 (1.2) 559.3 I-178 [00322] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5958 (4.1); 9.5789 (4.2); 8.4597 (5.9); 8.4561 (10.7); 8.4524 (6.0); 8.1402 (6.1); 8.1380 (5.9); 8.0983 (6.7); 6.0749 (0.6); 6.0577 (3.1); 6.0405 (4.9); 6.0232 (3.1); 6.0058 (0.6); 3.5373 (1.2); 3.4991 (2.0); 3.3662 (50.2); 3.3340 (323.5); 3.2182 (1.3); 3.1909 (1.2); 3.0920 (0.4); 2.9994 (0.7); 2.9900 (0.6); 2.6811 (0.4); 2.6769 (0.8); 2.6723 (1.1); 2.6677 (0.8); 2.6631 (0.4); 2.5258 (3.0); 2.5211 (4.5); 2.5124 (63.6); 2.5079 (131.4); 2.5033 (174.3); 2.4987 (124.2); 2.4942 (57.8); 2.3394 (0.3); 2.3347 (0.8); 2.3301 (1.0); 2.3255 (0.8); 2.3209 (0.3); 2.0958 (0.8); 2.0836 (1.9); 2.0749 (2.0); 2.0719 (1.6); 2.0629 (4.0); 2.0508 (2.3); 2.0422 (2.1); 2.0299 (1.0); 1.6209 (16.0); 1.6034 (15.9); 1.1522 (2.8); 1.0448 (0.4); 1.0323 (0.8); 1.0145 (5.7); 1.0108 (6.6); 0.9940 (5.9); 0.9897 (6.2); 0.9741 (1.0); 0.9617 (0.6); 0.9001 (0.8); 0.8913 (0.8); 0.8875 (0.8); 0.8798 (2.4); 0.8757 (2.8); 0.8703 (2.8); 0.8643 (4.6); 0.8583 (3.9); 0.8536 (3.3); 587.2 0.8435 (2.3); 0.8336 (0.7); 0.8295 (0.8); 0.8215 (0.5); 0.8181 (0.5); 0.0080 (1.1); −0.0001 (36.2); −0.0085 (1.0) I-179 [00323] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5935 (2.4); 9.5767 (2.5); 8.4619 (3.2); 8.4584 (5.8); 8.4549 (3.4); 8.2720 (4.9); 8.1421 (3.5); 8.1400 (3.4); 8.1002 (3.6); 6.0868 (0.4); 6.0693 (1.7); 6.0521 (2.6); 6.0348 (1.7); 6.0172 (0.4); 3.3653 (26.9); 3.3311 (73.6); 3.1563 (1.1); 3.0118 (16.0); 2.6766 (0.5); 2.6719 (0.7); 2.6673 (0.5); 2.5252 (2.6); 2.5119 (43.6); 2.5075 (86.7); 2.5030 (113.7); 2.4984 (82.6); 2.4940 (39.9); 2.3343 (0.5); 2.3298 (0.7); 2.3251 (0.5); 2.0945 (0.5); 2.0825 (1.1); 2.0738 (1.1); 2.0618 (2.2); 2.0497 (1.3); 2.0411 (1.1); 2.0289 (0.6); 1.6245 (8.8); 1.6070 (8.8); 1.0327 (0.4); 1.0153 (3.3); 1.0116 (3.8); 0.9948 (3.5); 0.9905 (3.6); 0.9757 (0.7); 0.9632 (0.3); 0.9044 (0.9); 0.8924 (1.6); 0.8818 (2.6); 0.8657 (4.7); 0.8601 (3.4); 0.8562 (3.3); 0.8358 (1.1); 0.8246 (0.7); 0.7742 (0.4); 0.7653 (0.7); 0.7526 (0.8); 0.7399 (1.3); 0.7310 (1.9); 0.7261 (2.1); 0.7221 (2.1); 0.7160 (1.9); 0.7053 (1.1); 0.6943 (0.6); 0.6807 (0.5); −0.0002 (5.5) 599.3 I-180 [00324] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6592 (3.2); 9.6422 (3.2); 8.7435 (0.9); 8.7328 (2.6); 8.7212 (2.5); 8.7098 (0.8); 8.6596 (5.8); 8.5227 (5.1); 8.4169 (5.2); 8.1967 (16.0); 6.0835 (0.5); 6.0668 (2.2); 6.0495 (3.4); 6.0322 (2.2); 6.0146 (0.4); 3.3877 (34.5); 3.3308 (436.6); 2.7961 (14.3); 2.7846 (14.1); 2.6804 (0.9); 2.6759 (1.9); 2.6713 (2.6); 2.6668 (1.9); 2.6623 (0.9); 2.5248 (8.4); 2.5201 (12.8); 2.5114 (153.8); 2.5069 (308.4); 2.5024 (400.2); 2.4978 (284.6); 2.4933 (133.9); 2.3382 (0.8); 2.3337 (1.8); 2.3292 (2.5); 2.3246 (1.8); 2.3202 (0.8); 2.0908 (0.6); 2.0787 (1.4); 2.0700 (1.4); 2.0581 (2.8); 2.0459 (1.6); 2.0373 (1.4); 2.0251 (0.7); 1.6199 (11.1); 1.6024 (11.0); 1.0300 (0.6); 1.0129 (4.1); 1.0094 (4.6); 0.9923 (4.1); 0.9885 (4.1); 0.9741 (0.8); 0.9603 (0.4); 0.8974 (0.4); 0.8796 (1.6); 0.8731 (2.1); 0.8671 (3.1); 0.8616 (3.6); 0.8568 (3.0); 0.8535 (2.8); 0.8455 (1.4); 0.8306 (0.5); 0.8220 (0.4); 0.0080 (1.9); −0.0001 (59.1); −0.0084 (1.7) 543.2 I-181 [00325] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4560 (2.5); 9.4394 (2.6); 8.6110 (16.0); 8.3689 (3.7); 8.3655 (6.7); 8.3620 (3.8); 8.2503 (3.4); 8.2482 (3.2); 8.0966 (3.2); 8.0941 (3.5); 8.0916 (3.0); 6.0104 (0.4); 5.9933 (1.8); 5.9763 (2.8); 5.9592 (1.9); 5.9421 (0.4); 3.3311 (186.8); 2.6810 (0.4); 2.6765 (0.8); 2.6719 (1.1); 2.6673 (0.8); 2.6625 (0.5); 2.5254 (3.7); 2.5207 (5.5); 2.5120 (67.0); 2.5075 (134.4); 2.5029 (174.2); 2.4983 (123.6); 2.4938 (58.1); 2.3388 (0.4); 2.3343 (0.8); 2.3298 (1.1); 2.3252 (0.8); 2.3205 (0.3); 2.1131 (0.5); 2.1010 (1.2); 2.0922 (1.2); 2.0893 (1.0); 2.0803 (2.5); 2.0761 (2.5); 2.0682 (1.4); 2.0596 (1.2); 2.0474 (0.6); 1.5961 (9.9); 1.5786 (9.8); 1.0561 (0.5); 1.0388 (3.5); 1.0349 (3.9); 1.0182 (3.5); 1.0139 (3.6); 0.9989 (0.6); 0.9114 (0.4); 0.9079 (0.4); 0.8995 (0.4); 0.8953 (0.5); 0.8884 (1.4); 0.8835 (1.7); 0.8759 (2.2); 0.8706 (2.8); 0.8662 (2.5); 0.8623 (2.1); 0.8581 (1.4); 0.8538 (1.3); 474.3 0.8509 (1.2); 0.8426 (0.4); 0.8386 (0.5); 0.1459 (0.5); 0.0080 (4.2); −0.0002 (128.5); −0.0085 (4.1); −0.1496 (0.5) I-182 [00326] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3914 (0.6); 9.3800 (2.9); 9.3632 (2.9); 8.7432 (0.8); 8.7327 (2.2); 8.7211 (2.2); 8.7100 (0.7); 8.1882 (16.0); 8.0010 (0.8); 7.9940 (4.5); 7.9901 (6.3); 7.9860 (4.2); 7.8017 (4.4); 7.7676 (4.3); 7.7649 (4.3); 7.7623 (3.3); 6.0059 (0.5); 6.0023 (0.5); 5.9891 (2.2); 5.9720 (3.3); 5.9548 (2.1); 5.9373 (0.4); 3.3347 (279.3); 2.7968 (14.1); 2.7854 (13.8); 2.6811 (0.7); 2.6765 (1.4); 2.6720 (2.0); 2.6674 (1.4); 2.6627 (0.7); 2.5255 (6.4); 2.5208 (9.4); 2.5121 (119.8); 2.5076 (242.2); 2.5030 (314.7); 2.4984 (221.9); 2.4938 (103.0); 2.3390 (0.6); 2.3344 (1.4); 2.3298 (1.9); 2.3252 (1.4); 2.3207 (0.6); 2.0859 (0.6); 2.0738 (1.4); 2.0652 (1.4); 2.0620 (1.1); 2.0580 (0.8); 2.0531 (2.8); 2.0444 (1.1); 2.0410 (1.6); 2.0324 (1.4); 2.0201 (0.7); 1.5847 (12.2); 1.5672 (12.1); 1.0309 (0.4); 1.0123 (4.0); 1.0074 (5.2); 0.9915 (3.9); 0.9865 (5.3); 515.0 0.9692 (0.6); 0.9593 (0.4); 0.8925 (0.6); 0.8837 (0.6); 0.8798 (0.7); 0.8690 (3.0); 0.8628 (1.6); 0.8567 (3.3); 0.8509 (2.5); 0.8448 (2.6); 0.8404 (1.7); 0.8327 (2.3); 0.8213 (0.6); 0.8171 (0.7); 0.8092 (0.5); 0.0080 (1.5); −0.0002 (54.4); −0.0085 (1.5) I-183 [00327] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3905 (4.1); 9.3735 (4.2); 8.0973 (0.6); 8.0005 (6.3); 7.9964 (9.2); 7.9923 (6.4); 7.8047 (5.7); 7.7787 (5.8); 7.7760 (5.9); 7.7734 (4.6); 6.0240 (0.6); 6.0066 (3.0); 5.9894 (4.8); 5.9721 (3.1); 5.9548 (0.6); 5.7592 (0.7); 5.3363 (0.6); 5.3243 (1.1); 5.3130 (0.6); 3.5014 (2.0); 3.4376 (0.4); 3.3297 (424.9); 3.2216 (1.2); 3.1481 (0.6); 3.1001 (0.4); 3.0015 (0.6); 2.6806 (1.0); 2.6761 (2.1); 2.6715 (2.9); 2.6669 (2.1); 2.6624 (1.0); 2.5251 (9.6); 2.5204 (14.1); 2.5117 (173.4); 2.5072 (349.9); 2.5026 (453.6); 2.4979 (318.5); 2.4934 (146.9); 2.3385 (0.9); 2.3340 (2.0); 2.3294 (2.8); 2.3248 (2.0); 2.3203 (0.8); 2.0906 (0.8); 2.0785 (1.9); 2.0697 (2.0); 2.0666 (1.5); 2.0577 (4.0); 2.0456 (2.3); 2.0370 (2.1); 2.0253 (1.6); 2.0086 (2.0); 1.9895 (1.9); 1.9735 (0.9); 1.9570 (0.4); 1.5946 (16.0); 1.5772 (15.9); 1.4728 (0.5); 1.4554 (0.6); 1.4370 (0.5); 1.2893 (1.0); 1.2343 (12.9); 1.1498 (2.9); 543.0 1.1066 (0.9); 1.0729 (0.4); 1.0554 (0.5); 1.0410 (0.4); 1.0379 (0.5); 1.0324 (0.5); 1.0148 (3.6); 1.0117 (5.1); 1.0070 (6.3); 0.9909 (4.7); 0.9861 (6.5); 0.9674 (0.7); 0.9583 (0.5); 0.8937 (0.9); 0.8853 (1.0); 0.8818 (1.0); 0.8702 (5.0); 0.8644 (2.7); 0.8578 (5.1); 0.8535 (5.7); 0.8444 (3.4); 0.8394 (2.7); 0.8354 (3.4); 0.8205 (0.9); 0.8164 (1.2); 0.8085 (0.7); 0.8048 (0.6); 0.1459 (0.4); 0.0081 (2.9); −0.0001 (98.2); −0.0085 (2.7); −0.1498 (0.4) I-184 [00328] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4336 (2.9); 9.4169 (2.9); 8.2520 (13.2); 8.1604 (16.0); 7.7461 (4.4); 7.7437 (4.2); 7.7357 (4.2); 7.7307 (4.8); 7.5674 (3.3); 7.4872 (4.1); 7.3846 (7.0); 7.2017 (3.5); 6.0935 (0.4); 6.0762 (2.0); 6.0592 (3.1); 6.0420 (2.0); 6.0247 (0.4); 5.7593 (3.3); 4.0560 (0.4); 4.0383 (1.1); 4.0205 (1.2); 4.0027 (0.4); 3.3342 (161.4); 3.2511 (2.6); 3.1397 (0.3); 3.1228 (0.4); 3.0279 (2.5); 2.6769 (0.5); 2.6724 (0.7); 2.6678 (0.5); 2.5258 (2.2); 2.5209 (3.5); 2.5123 (43.8); 2.5079 (87.5); 2.5034 (113.6); 2.4988 (81.1); 2.4943 (38.2); 2.3348 (0.5); 2.3303 (0.7); 2.3256 (0.5); 1.9900 (5.0); 1.6426 (11.7); 1.6252 (11.6); 1.1930 (1.4); 1.1752 (2.7); 1.1574 (1.3); 0.8882 (0.3); 0.8714 (0.4); 0.0079 (0.4); −0.0002 (13.3); −0.0086 (0.4) 521.0 I-185 [00329] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5398 (2.8); 9.5231 (2.9); 9.0491 (6.4); 9.0448 (6.4); 8.8598 (3.8); 8.8536 (3.8); 8.7968 (0.8); 8.7866 (2.2); 8.7750 (2.2); 8.7641 (0.7); 8.2615 (13.2); 8.2458 (16.0); 8.2395 (3.2); 8.2375 (3.4); 8.2353 (3.9); 8.2330 (3.4); 6.0980 (0.4); 6.0808 (2.0); 6.0637 (3.0); 6.0466 (2.0); 6.0295 (0.4); 3.3338 (119.5); 2.8064 (14.1); 2.7949 (13.9); 2.6767 (0.6); 2.6721 (0.9); 2.6677 (0.6); 2.5257 (2.8); 2.5209 (4.3); 2.5123 (52.7); 2.5078 (105.5); 2.5033 (137.2); 2.4986 (97.6); 2.4941 (45.6); 2.3346 (0.6); 2.3301 (0.8); 2.3255 (0.6); 1.9899 (0.3); 1.6427 (11.6); 1.6252 (11.5); 0.0079 (0.4); −0.0003 (11.9) 442.2 I-186 [00330] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4196 (1.4); 9.4030 (1.5); 8.7920 (0.4); 8.7818 (1.2); 8.7701 (1.2); 8.7589 (0.4); 8.2529 (7.0); 8.2431 (8.0); 7.8370 (1.9); 7.8332 (3.3); 7.8294 (2.1); 7.7594 (1.8); 7.7569 (2.1); 7.7544 (1.9); 7.4949 (2.1); 6.0674 (1.0); 6.0503 (1.5); 6.0331 (1.0); 3.3325 (84.8); 2.8077 (7.4); 2.7962 (7.3); 2.6768 (0.3); 2.6723 (0.5); 2.6676 (0.3); 2.5258 (1.4); 2.5210 (2.2); 2.5123 (27.7); 2.5078 (56.4); 2.5033 (73.8); 2.4987 (52.7); 2.4941 (24.8); 2.3300 (0.4); 2.0764 (16.0); 1.8592 (1.1); 1.8468 (3.2); 1.8392 (3.4); 1.8278 (1.5); 1.6656 (1.7); 1.6532 (3.5); 1.6457 (3.7); 1.6385 (5.9); 1.6210 (5.7); −0.0002 (6.6) 506.0 I-187 [00331] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4217 (2.8); 9.4051 (2.9); 8.7946 (0.8); 8.7838 (2.2); 8.7723 (2.2); 8.7613 (0.7); 8.2496 (13.7); 8.2422 (16.0); 7.7306 (4.6); 7.7258 (6.8); 7.7207 (5.1); 7.5623 (3.5); 7.4839 (3.9); 7.3795 (7.5); 7.1966 (3.7); 6.0758 (0.4); 6.0585 (1.9); 6.0414 (3.0); 6.0243 (1.9); 6.0072 (0.4); 3.3436 (681.3); 2.8070 (14.4); 2.7955 (14.2); 2.6815 (0.5); 2.6770 (1.0); 2.6724 (1.4); 2.6678 (1.0); 2.6635 (0.5); 2.5259 (4.3); 2.5212 (6.3); 2.5125 (81.0); 2.5080 (165.1); 2.5034 (216.6); 2.4988 (154.1); 2.4943 (72.0); 2.3393 (0.4); 2.3348 (1.0); 2.3302 (1.3); 2.3256 (1.0); 2.3212 (0.4); 2.0868 (9.0); 1.6319 (11.3); 1.6144 (11.2); 1.2336 (0.6); −0.0002 (4.4) 507.2 I-188 [00332] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6010 (2.7); 9.5839 (2.8); 8.4608 (3.8); 8.4572 (7.0); 8.4536 (3.9); 8.2205 (3.9); 8.1427 (3.9); 8.1403 (3.7); 8.1145 (16.0); 8.0984 (3.9); 6.0765 (0.4); 6.0592 (2.0); 6.0420 (3.1); 6.0247 (2.0); 6.0071 (0.4); 3.5392 (0.6); 3.3669 (32.6); 3.2414 (2.4); 3.1915 (1.1); 3.1660 (0.8); 3.1481 (0.9); 3.1324 (0.9); 3.1175 (0.8); 3.1009 (0.7); 3.0227 (2.0); 2.6767 (0.5); 2.6722 (0.7); 2.6676 (0.5); 2.6139 (0.4); 2.5957 (0.4); 2.5257 (1.8); 2.5210 (2.7); 2.5123 (35.7); 2.5078 (72.5); 2.5032 (95.8); 2.4986 (68.8); 2.4941 (32.3); 2.3346 (0.4); 2.3301 (0.6); 2.3255 (0.4); 2.0942 (0.6); 2.0819 (1.3); 2.0733 (1.3); 2.0702 (1.0); 2.0613 (2.6); 2.0491 (1.5); 2.0405 (1.4); 2.0283 (0.7); 1.6210 (10.3); 1.6035 (10.3); 1.0340 (9.8); 1.0175 (12.5); 1.0110 (5.3); 0.9941 (4.0); 0.9897 (4.0); 0.9743 (0.7); 0.9621 (0.4); 0.9002 (0.5); 0.8915 (0.5); 0.8874 (0.6); 0.8800 (1.5); 0.8757 (1.8); 0.8643 (3.0); 0.8583 (2.6); 0.8538 (2.2); 0.8439 (1.4); 0.8338 (0.4); 0.8299 (0.5); 0.8218 (0.4); −0.0002 (5.9) 573.3 I-189 [00333] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5548 (3.8); 9.5382 (4.0); 9.0558 (8.2); 9.0518 (8.2); 8.8603 (5.7); 8.8549 (5.8); 8.2613 (15.4); 8.2504 (6.2); 8.1638 (16.0); 6.1149 (0.6); 6.0979 (2.6); 6.0811 (4.0); 6.0639 (2.6); 6.0463 (0.7); 3.3547 (2215.2); 3.2540 (5.9); 3.0277 (4.6); 2.6727 (3.5); 2.5081 (430.2); 2.5039 (520.4); 2.4997 (388.4); 2.3306 (3.2); 1.6519 (15.3); 1.6344 (15.2); −0.0001 (4.3) 456.3 I-190 [00334] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4329 (2.5); 9.4161 (2.6); 8.2547 (12.1); 8.1596 (16.0); 7.8512 (3.3); 7.8475 (5.6); 7.8436 (3.5); 7.7737 (3.2); 7.7711 (3.6); 7.7686 (3.2); 7.4956 (3.6); 6.1008 (0.4); 6.0834 (1.6); 6.0662 (2.6); 6.0490 (1.7); 6.0318 (0.4); 3.3879 (0.4); 3.3785 (0.7); 3.3468 (335.2); 3.2944 (0.4); 3.2470 (2.2); 3.0279 (2.1); 2.6779 (0.4); 2.6734 (0.6); 2.6689 (0.4); 2.5269 (1.6); 2.5221 (2.5); 2.5135 (35.2); 2.5090 (71.0); 2.5045 (92.1); 2.4998 (65.4); 2.4953 (30.5); 2.3359 (0.4); 2.3313 (0.6); 2.3267 (0.4); 2.0764 (4.6); 1.8614 (1.9); 1.8488 (5.6); 1.8413 (6.0); 1.8297 (2.6); 1.7905 (0.4); 1.6696 (2.7); 1.6569 (6.5); 1.6492 (14.7); 1.6314 (9.8); −0.0002 (1.0) 520.3 I-191 [00335] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4992 (1.3); 9.4827 (1.3); 8.6322 (8.4); 7.9357 (3.7); 7.9308 (3.8); 7.7815 (1.6); 6.0292 (1.0); 6.0121 (1.5); 5.9951 (1.0); 3.3324 (94.9); 2.6722 (0.4); 2.5258 (1.3); 2.5210 (2.1); 2.5123 (25.7); 2.5078 (52.1); 2.5033 (68.7); 2.4986 (49.3); 2.4941 (23.2); 2.3471 (16.0); 2.3349 (0.5); 2.3300 (0.5); 2.3256 (0.3); 1.6184 (5.3); 1.6009 (5.3); 0.0081 (0.7); −0.0002 (22.2); −0.0085 (0.6) 507.0 I-192 [00336] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.4634 (2.7); 9.4469 (2.8); 8.6114 (16.0); 7.8896 (7.5); 7.8848 (7.9); 7.7768 (3.4); 6.0007 (0.4); 5.9833 (2.0); 5.9663 (3.0); 5.9492 (2.0); 5.9318 (0.4); 3.3307 (289.4); 2.6808 (0.6); 2.6762 (1.3); 2.6717 (1.8); 2.6671 (1.3); 2.6626 (0.6); 2.5251 (5.9); 2.5204 (8.9); 2.5118 (103.9); 2.5073 (208.1); 2.5028 (270.4); 2.4982 (191.8); 2.4937 (90.3); 2.3386 (0.5); 2.3341 (1.2); 2.3296 (1.7); 2.3250 (1.2); 2.3205 (0.5); 2.1130 (0.5); 2.1010 (1.2); 2.0923 (1.3); 2.0803 (2.6); 2.0683 (1.5); 2.0595 (1.3); 2.0474 (0.6); 1.5963 (10.8); 1.5788 (10.7); 1.3974 (0.9); 1.2583 (0.4); 1.0381 (3.3); 1.0335 (4.0); 1.0173 (3.1); 1.0127 (4.2); 0.9938 (0.4); 0.9846 (0.3); 0.9100 (0.4); 0.9062 (0.6); 0.8993 (0.6); 0.8938 (0.6); 0.8826 (2.5); 0.8767 (1.4); 0.8704 (2.7); 0.8642 (2.2); 0.8569 (2.1); 0.8521 (1.4); 0.8449 (1.9); 0.8333 (0.5); 0.8289 (0.8); 0.8213 (0.4); 0.8169 (0.4); 0.0079 (1.5); −0.0003 (47.1); −0.0086 (1.4) 533.0 I-193 [00337] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3855 (2.4); 9.3687 (2.5); 8.2649 (5.0); 8.1647 (0.4); 8.0002 (3.4); 7.9962 (5.2); 7.9922 (3.4); 7.8044 (3.4); 7.7797 (3.5); 7.7771 (3.5); 6.0331 (0.4); 6.0160 (1.7); 5.9987 (2.7); 5.9815 (1.7); 5.9644 (0.4); 3.3334 (83.0); 3.1571 (1.1); 3.0119 (16.0); 2.6764 (0.8); 2.6719 (1.2); 2.6673 (0.8); 2.6627 (0.4); 2.5254 (3.9); 2.5205 (5.9); 2.5119 (69.4); 2.5075 (136.3); 2.5029 (174.6); 2.4983 (124.6); 2.4939 (59.2); 2.3384 (0.4); 2.3342 (0.8); 2.3297 (1.1); 2.3252 (0.8); 2.0900 (0.4); 2.0777 (1.1); 2.0691 (1.2); 2.0571 (2.2); 2.0451 (1.3); 2.0364 (1.1); 2.0243 (0.6); 1.5991 (9.1); 1.5816 (9.0); 1.0136 (3.0); 1.0087 (3.8); 0.9928 (2.9); 0.9878 (3.9); 0.9699 (0.4); 0.9048 (0.6); 0.8849 (1.7); 0.8730 (3.7); 0.8675 (3.1); 0.8607 (3.4); 0.8550 (3.2); 0.8512 (2.9); 0.8483 (3.1); 0.8358 (2.3); 0.8244 (0.8); 0.8200 (0.8); 0.7745 (0.4); 0.7653 (0.7); 0.7521 (0.8); 0.7407 (1.3); 0.7358 (1.3); 0.7308 (1.8); 0.7256 (1.9); 0.7213 (1.8); 0.7147 (1.8); 0.7038 555.3 (1.2); 0.6935 (0.7); 0.6795 (0.5); 0.0078 (0.6); −0.0003 (20.1); −0.0086 (0.6) I-194 [00338] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3677 (3.2); 9.3507 (3.4); 8.7458 (0.9); 8.7349 (2.7); 8.7232 (2.7); 8.7125 (0.8); 8.1911 (16.0); 7.8112 (4.4); 7.8076 (7.2); 7.8038 (4.5); 7.7318 (4.8); 7.4900 (5.0); 6.0211 (0.5); 6.0039 (2.3); 5.9867 (3.6); 5.9694 (2.3); 5.9519 (0.5); 3.3341 (522.6); 2.7976 (15.2); 2.7862 (15.0); 2.6763 (1.8); 2.6718 (2.5); 2.6672 (1.8); 2.6627 (0.8); 2.5252 (8.1); 2.5203 (12.9); 2.5117 (152.1); 2.5073 (298.6); 2.5028 (384.3); 2.4982 (278.0); 2.4938 (134.6); 2.3342 (1.9); 2.3296 (2.6); 2.3252 (1.8); 2.3206 (0.9); 2.0864 (0.7); 2.0742 (1.6); 2.0655 (1.7); 2.0534 (3.1); 2.0413 (1.9); 2.0327 (1.7); 2.0205 (0.9); 1.8602 (2.4); 1.8484 (6.6); 1.8407 (7.6); 1.8296 (3.2); 1.7895 (0.4); 1.7045 (0.4); 1.6651 (3.8); 1.6530 (7.2); 1.6455 (6.5); 1.6329 (2.8); 1.5957 (12.2); 1.5782 (12.2); 1.5566 (0.4); 1.2322 (0.4); 1.0294 (0.4); 1.0107 (4.2); 1.0059 (5.3); 0.9899 (4.2); 0.9850 (5.3); 0.9678 (0.7); 0.9583 (0.4); 0.8926 (0.7); 0.8804 (0.8); 0.8691 (3.0); 0.8628 (1.9); 0.8568 (3.5); 0.8517 (2.9); 0.8452 (2.8); 0.8408 (2.0); 0.8333 (2.5); 0.8176 (0.8); 0.8095 (0.6); −0.0001 (7.7) 546.3 I-195 [00339] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3965 (2.8); 9.3796 (2.8); 8.1360 (1.7); 8.1092 (16.0); 8.0031 (4.0); 7.9991 (6.1); 7.9951 (4.1); 7.8049 (3.9); 7.7810 (4.0); 7.7784 (4.1); 7.7759 (3.2); 6.0259 (0.4); 6.0087 (2.0); 5.9915 (3.1); 5.9743 (2.0); 5.9573 (0.4); 3.3385 (379.2); 3.2445 (2.1); 3.0222 (2.1); 2.6812 (0.6); 2.6768 (1.2); 2.6722 (1.6); 2.6677 (1.1); 2.6631 (0.5); 2.5257 (5.7); 2.5209 (9.0); 2.5122 (93.0); 2.5078 (183.2); 2.5032 (237.4); 2.4986 (171.3); 2.4941 (82.4); 2.3391 (0.5); 2.3346 (1.1); 2.3300 (1.5); 2.3254 (1.1); 2.3210 (0.5); 2.0888 (0.5); 2.0767 (1.2); 2.0680 (1.3); 2.0648 (1.1); 2.0560 (2.6); 2.0438 (1.5); 2.0352 (1.4); 2.0230 (0.7); 1.5947 (10.5); 1.5772 (10.6); 1.0122 (3.4); 1.0074 (4.2); 0.9914 (3.1); 0.9865 (4.4); 0.9682 (0.5); 0.9593 (0.4); 0.8933 (0.6); 0.8853 (0.6); 0.8811 (0.6); 0.8697 (2.6); 0.8640 (1.5); 0.8574 (2.8); 0.8515 (2.4); 529.2 0.8443 (2.1); 0.8392 (1.5); 0.8320 (1.9); 0.8204 (0.6); 0.8159 (0.7); 0.8083 (0.4); 0.0080 (1.7); −0.0002 (46.6); −0.0085 (1.6) I-196 [00340] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6766 (3.0); 9.6595 (3.1); 8.6673 (5.6); 8.5381 (5.0); 8.4204 (5.0); 8.1842 (1.5); 8.1194 (16.0); 6.1013 (0.4); 6.0841 (2.0); 6.0668 (3.2); 6.0495 (2.0); 6.0323 (0.4); 3.3914 (31.9); 3.3354 (8.2); 3.2435 (2.6); 3.1048 (0.5); 3.0233 (2.3); 2.6897 (0.7); 2.6769 (0.6); 2.6724 (0.9); 2.6678 (0.6); 2.5257 (3.2); 2.5123 (51.1); 2.5079 (98.8); 2.5034 (126.7); 2.4988 (91.5); 2.4944 (44.1); 2.3347 (0.6); 2.3302 (0.8); 2.3258 (0.6); 2.0953 (0.6); 2.0831 (1.3); 2.0744 (1.4); 2.0624 (2.6); 2.0504 (1.5); 2.0417 (1.4); 2.0296 (0.7); 1.6311 (10.6); 1.6136 (10.5); 1.0441 (1.7); 1.0273 (1.9); 1.0140 (4.4); 1.0109 (4.7); 0.9935 (4.1); 0.9900 (4.1); 0.9745 (0.7); 0.9614 (0.4); 0.9007 (0.5); 0.8920 (0.6); 0.8887 (0.6); 0.8818 (1.6); 0.8757 (2.0); 0.8696 (2.8); 0.8639 (3.4); 0.8593 (3.0); 0.8552 (2.6); 0.8467 (1.4); 0.8359 (0.5); 0.8320 (0.6); 0.8235 (0.4); 0.0080 (0.8); −0.0002 (22.9); −0.0084 (0.7) 557.2 I-197 [00341] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3816 (2.8); 9.3646 (2.9); 8.1106 (16.0); 7.8252 (3.7); 7.8214 (6.3); 7.8176 (4.1); 7.7475 (3.6); 7.7448 (4.1); 7.7423 (3.7); 7.4905 (4.3); 6.0382 (0.4); 6.0210 (2.0); 6.0037 (3.2); 5.9864 (2.0); 5.9692 (0.4); 3.3333 (215.2); 3.2386 (2.1); 3.0219 (2.1); 2.6807 (0.6); 2.6763 (1.3); 2.6717 (1.8); 2.6672 (1.2); 2.6627 (0.6); 2.5253 (6.1); 2.5205 (9.3); 2.5118 (103.6); 2.5073 (204.3); 2.5028 (263.4); 2.4981 (188.7); 2.4936 (89.3); 2.3387 (0.6); 2.3341 (1.2); 2.3296 (1.7); 2.3250 (1.2); 2.3207 (0.5); 2.0897 (0.5); 2.0766 (2.1); 2.0689 (1.4); 2.0658 (1.1); 2.0569 (2.6); 2.0447 (1.5); 2.0361 (1.4); 2.0240 (0.7); 1.8622 (2.1); 1.8502 (6.0); 1.8426 (6.8); 1.8312 (2.8); 1.7914 (0.4); 1.7091 (0.3); 1.6700 (3.0); 1.6576 (6.4); 1.6505 (6.2); 1.6372 (2.2); 1.6053 (10.5); 1.5878 (10.5); 1.0295 (0.5); 1.0109 (3.6); 1.0061 (4.4); 0.9901 (3.4); 0.9852 (4.6); 0.9670 (0.5); 0.9582 (0.3); 0.8944 (0.6); 0.8867 (0.6); 0.8820 (0.7); 0.8708 (2.8); 0.8648 (1.5); 0.8585 (3.0); 0.8527 (2.5); 0.8457 (2.2); 0.8407 560.3 (1.5); 0.8336 (2.0); 0.8176 (0.8); 0.8098 (0.5); 0.0080 (1.3); −0.0002 (39.2); −0.0085 (1.1) I-198 [00342] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3784 (4.3); 9.3612 (4.4); 8.0987 (0.7); 7.8237 (5.8); 7.8199 (9.4); 7.8162 (5.8); 7.7451 (5.5); 7.7426 (6.1); 7.4901 (6.4); 6.0359 (0.7); 6.0186 (3.1); 6.0013 (4.8); 5.9840 (3.1); 5.9664 (0.6); 3.5033 (2.3); 3.3317 (321.1); 3.2842 (0.4); 3.2080 (1.5); 3.1178 (0.5); 3.1073 (0.5); 3.0982 (0.5); 2.9931 (0.8); 2.6804 (1.1); 2.6760 (2.3); 2.6715 (3.1); 2.6669 (2.2); 2.6623 (1.0); 2.5250 (11.7); 2.5202 (18.3); 2.5115 (185.6); 2.5071 (362.9); 2.5025 (466.0); 2.4979 (334.5); 2.4934 (158.5); 2.3384 (1.0); 2.3339 (2.1); 2.3294 (2.8); 2.3248 (2.0); 2.3207 (0.9); 2.0916 (0.8); 2.0795 (2.0); 2.0763 (1.5); 2.0707 (2.1); 2.0678 (1.6); 2.0588 (4.0); 2.0466 (2.3); 2.0380 (2.1); 2.0258 (1.0); 1.8621 (3.1); 1.8502 (8.9); 1.8425 (10.1); 1.8313 (4.2); 1.7916 (0.5); 1.7083 (0.5); 1.6692 (4.8); 1.6568 (9.6); 1.6497 (9.1); 1.6365 (3.5); 1.6051 (16.0); 1.5877 (15.9); 1.2330 (0.5); 1.1504 (3.2); 1.0403 (0.4); 1.0309 (0.5); 1.0106 (5.4); 1.0059 (6.7); 0.9898 (5.1); 0.9850 (6.8); 0.9668 (0.8); 0.9576 (0.6); 0.8947 (0.9); 574.3 0.8864 (1.0); 0.8820 (1.0); 0.8708 (4.0); 0.8649 (2.3); 0.8586 (4.4); 0.8528 (3.8); 0.8457 (3.3); 0.8409 (2.3); 0.8337 (3.0); 0.8223 (0.9); 0.8178 (1.1); 0.8100 (0.7); 0.0079 (2.3); −0.0002 (65.6); −0.0085 (2.1) I-199 [00343] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3776 (2.6); 9.3606 (2.7); 8.2692 (5.0); 8.1514 (0.5); 7.8291 (3.2); 7.8256 (5.2); 7.8219 (3.2); 7.7462 (3.6); 7.4909 (3.7); 6.0486 (0.3); 6.0312 (1.6); 6.0139 (2.6); 5.9965 (1.6); 5.9791 (0.4); 3.3328 (58.7); 3.1551 (1.1); 3.0120 (16.0); 2.8915 (0.4); 2.7319 (0.4); 2.6769 (0.6); 2.6723 (0.8); 2.6678 (0.6); 2.5256 (3.0); 2.5120 (52.3); 2.5078 (100.4); 2.5033 (127.7); 2.4988 (92.5); 2.4946 (45.0); 2.3346 (0.6); 2.3301 (0.8); 2.3256 (0.6); 2.0911 (0.5); 2.0782 (1.2); 2.0701 (1.2); 2.0581 (2.1); 2.0461 (1.3); 2.0375 (1.1); 2.0252 (0.6); 1.8630 (1.7); 1.8510 (4.9); 1.8433 (5.5); 1.8321 (2.3); 1.6673 (2.7); 1.6552 (5.3); 1.6481 (4.9); 1.6351 (2.1); 1.6105 (8.7); 1.5930 (8.7); 1.0124 (3.0); 1.0076 (3.8); 0.9916 (3.0); 0.9868 (3.8); 0.9692 (0.4); 0.9058 (0.6); 0.8968 (1.3); 0.8854 (1.7); 0.8737 (3.5); 0.8673 (3.0); 0.8619 (4.0); 0.8560 (3.3); 0.8492 (3.2); 0.8382 (2.4); 0.8219 (1.0); 0.8132 (0.7); 0.7735 (0.4); 0.7633 (0.7); 0.7494 (0.8); 0.7390 (1.4); 0.7339 (1.3); 0.7282 (1.7); 0.7192 (1.7); 0.7092 (1.6); 0.6976 (1.2); 0.6876 (0.8); 0.6730 (0.5); 0.0079 (0.7); −0.0002 (20.5); −0.0085 (0.7) 586.3 I-200 [00344] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6586 (1.2); 9.6422 (1.2); 8.6173 (7.9); 8.4504 (1.8); 8.4467 (3.2); 8.4431 (1.8); 8.1718 (1.8); 8.1694 (1.6); 8.0800 (1.7); 6.0152 (0.9); 5.9983 (1.3); 5.9813 (0.9); 3.9708 (16.0); 3.5685 (1.6); 3.3259 (58.8); 3.0626 (0.6); 3.0549 (0.6); 3.0505 (0.4); 3.0431 (1.2); 3.0350 (0.4); 3.0312 (0.6); 3.0234 (0.6); 2.6763 (0.5); 2.6716 (0.7); 2.6670 (0.5); 2.5252 (2.0); 2.5204 (3.1); 2.5118 (39.3); 2.5073 (81.3); 2.5027 (106.4); 2.4981 (74.2); 2.4935 (34.0); 2.3340 (0.4); 2.3295 (0.6); 2.3249 (0.4); 1.6333 (4.8); 1.6158 (4.8); 1.2482 (1.0); 1.2325 (1.4); 1.2149 (1.8); 1.2103 (1.6); 1.2031 (1.6); 1.1984 (0.9); 1.1934 (1.0); 1.1851 (0.4); 1.1333 (0.5); 1.1203 (1.6); 1.1134 (1.4); 1.1003 (1.5); 1.0948 (1.2); 0.1459 (0.4); 0.0080 (4.3); −0.0002 (122.6); −0.0086 (3.7); −0.0143 (0.4); −0.1496 (0.5) 543.1 I-201 [00345] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.7858 (3.1); 9.7695 (3.1); 8.6672 (16.0); 8.5128 (7.0); 8.3791 (4.6); 8.3394 (13.3); 8.1438 (4.6); 7.5823 (2.4); 7.4525 (5.5); 7.3227 (2.8); 6.1022 (0.5); 6.0852 (2.1); 6.0682 (3.1); 6.0512 (2.1); 6.0345 (0.4); 3.3306 (271.4); 2.6761 (1.4); 2.6715 (1.8); 2.6671 (1.3); 2.5249 (6.0); 2.5114 (114.6); 2.5071 (223.3); 2.5026 (287.2); 2.4981 (207.8); 2.4937 (100.6); 2.3339 (1.3); 2.3294 (1.8); 2.3249 (1.3); 2.0759 (7.1); 1.6560 (12.4); 1.6385 (12.3); 1.2340 (0.4); 0.0079 (0.7); −0.0002 (19.6); −0.0084 (0.6) 523.1 I-202 [00346] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6236 (1.3); 9.6070 (1.4); 8.7488 (0.4); 8.7375 (1.1); 8.7260 (1.1); 8.7155 (0.4); 8.4803 (2.0); 8.4768 (3.4); 8.4732 (1.9); 8.1968 (6.8); 8.1557 (2.0); 8.1047 (2.0); 6.0290 (1.0); 6.0120 (1.4); 5.9949 (1.0); 3.9511 (16.0); 3.3655 (15.4); 3.3315 (169.0); 2.7984 (6.4); 2.7869 (6.3); 2.6758 (1.0); 2.6713 (1.3); 2.6667 (1.0); 2.6622 (0.4); 2.5247 (4.3); 2.5198 (6.9); 2.5112 (81.3); 2.5068 (158.7); 2.5023 (203.3); 2.4977 (146.3); 2.4932 (70.1); 2.3337 (1.0); 2.3291 (1.3); 2.3246 (0.9); 1.6285 (5.0); 1.6110 (5.0); −0.0002 (6.0) 549.0 I-203 [00347] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6346 (1.4); 9.6181 (1.4); 8.4855 (1.9); 8.4819 (3.3); 8.4784 (1.9); 8.1671 (2.0); 8.1649 (1.8); 8.1203 (7.8); 8.1056 (2.0); 6.0441 (1.0); 6.0271 (1.4); 6.0100 (1.0); 3.9528 (16.0); 3.3668 (15.7); 3.3311 (102.4); 3.2545 (1.0); 3.1912 (0.3); 3.0275 (0.9); 2.6759 (0.6); 2.6714 (0.9); 2.6667 (0.6); 2.5248 (2.7); 2.5198 (4.5); 2.5113 (53.0); 2.5069 (104.2); 2.5024 (134.5); 2.4978 (97.0); 2.4933 (46.6); 2.3336 (0.6); 2.3292 (0.8); 2.3247 (0.6); 1.6394 (5.1); 1.6219 (5.1); −0.0002 (4.3) 563.0 I-204 [00348] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6306 (1.7); 9.6141 (1.7); 8.4833 (3.7); 8.2803 (3.2); 8.1667 (2.4); 8.1071 (2.5); 6.0547 (1.0); 6.0377 (1.6); 6.0206 (1.1); 3.9538 (16.0); 3.3656 (16.8); 3.3301 (180.2); 3.1643 (0.7); 3.0148 (10.1); 2.6753 (1.1); 2.6710 (1.5); 2.6667 (1.1); 2.5064 (177.1); 2.5021 (223.6); 2.4977 (164.9); 2.3332 (1.0); 2.3289 (1.4); 2.3245 (1.0); 1.9884 (0.4); 1.6424 (5.8); 1.6249 (5.8); 1.2342 (0.5); 1.2289 (0.5); 1.2175 (0.4); 1.2126 (0.3); 0.9154 (0.4); 0.8954 (1.2); 0.8856 (1.6); 0.8785 (1.3); 0.8694 (1.4); 0.8518 (0.5); 0.7734 (0.4); 0.7615 (0.5); 0.7441 (1.4); 0.7361 (2.1); 0.7100 (0.4); −0.0003 (5.4) 589.3 I-205 [00349] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.3972 (2.7); 9.3803 (2.8); 8.1378 (5.0); 8.1337 (6.5); 8.1299 (3.9); 8.1105 (16.0); 7.9087 (3.9); 7.8102 (3.7); 7.8076 (4.1); 7.8050 (3.5); 6.0265 (0.4); 6.0095 (2.0); 5.9923 (3.1); 5.9751 (2.0); 5.9575 (0.4); 3.3357 (35.4); 3.2461 (2.1); 3.1374 (0.4); 3.1337 (0.4); 3.0245 (2.0); 2.6784 (0.4); 2.6738 (0.5); 2.6694 (0.4); 2.5273 (1.8); 2.5226 (2.9); 2.5139 (34.3); 2.5094 (67.4); 2.5049 (86.4); 2.5002 (61.8); 2.4957 (29.3); 2.3363 (0.4); 2.3316 (0.5); 2.3273 (0.4); 2.0903 (0.5); 2.0782 (1.6); 2.0695 (1.3); 2.0665 (1.0); 2.0575 (2.6); 2.0454 (1.5); 2.0368 (1.4); 2.0245 (0.7); 1.5951 (10.4); 1.5776 (10.4); 1.0131 (3.4); 1.0084 (4.2); 0.9923 (3.2); 0.9875 (4.3); 0.9689 (0.5); 0.9600 (0.4); 0.8957 (0.6); 0.8879 (0.6); 0.8835 (0.6); 0.8721 (2.6); 0.8664 (1.4); 0.8598 (2.8); 0.8539 (2.3); 0.8465 (2.1); 0.8416 (1.5); 0.8346 (1.9); 0.8226 (0.6); 575.0 0.8185 (0.7); 0.8104 (0.4); 0.8070 (0.4); 0.0080 (1.2); −0.0002 (33.0); −0.0085 (0.9) I-206 [00350] 1H-NMR(400.2 MHz, d6-DMSO): δ = 9.6216 (3.0); 9.6046 (3.1); 8.4265 (4.1); 8.4231 (7.0); 8.4196 (3.9); 8.1535 (4.2); 8.1136 (16.0); 8.0764 (4.3); 6.0762 (0.4); 6.0588 (2.1); 6.0416 (3.2); 6.0244 (2.0); 6.0070 (0.4); 3.3338 (285.5); 3.3014 (0.5); 3.2388 (2.3); 3.0736 (1.2); 3.0616 (2.2); 3.0538 (2.4); 3.0492 (2.1); 3.0421 (4.2); 3.0301 (3.5); 3.0224 (3.6); 3.0106 (2.5); 2.6765 (1.1); 2.6719 (1.5); 2.6674 (1.1); 2.6631 (0.5); 2.5253 (5.2); 2.5205 (8.0); 2.5119 (95.5); 2.5075 (188.2); 2.5030 (241.7); 2.4984 (172.9); 2.4940 (83.0); 2.3388 (0.5); 2.3342 (1.1); 2.3297 (1.5); 2.3253 (1.1); 2.3208 (0.5); 2.0957 (0.6); 2.0836 (1.3); 2.0761 (2.4); 2.0629 (2.6); 2.0508 (1.5); 2.0421 (1.4); 2.0298 (0.7); 1.6215 (10.7); 1.6040 (10.7); 1.2492 (0.4); 1.2372 (0.5); 1.2253 (1.8); 1.2151 (3.7); 1.2042 (3.6); 1.1984 (2.0); 1.1948 (2.4); 1.1855 (0.7); 1.1737 (0.6); 1.1593 (0.5); 1.1480 (0.4); 1.1416 (0.4); 1.1337 (1.0); 1.1211 (3.4); 1.1137 599.2 (3.1); 1.1012 (3.3); 1.0956 (2.5); 1.0932 (2.5); 1.0801 (0.5); 1.0342 (0.5); 1.0154 (3.7); 1.0116 (4.5); 0.9948 (3.9); 0.9906 (4.4); 0.9741 (0.6); 0.9628 (0.4); 0.9012 (0.6); 0.8928 (0.6); 0.8884 (0.6); 0.8778 (2.0); 0.8641 (3.2); 0.8597 (2.8); 0.8554 (2.3); 0.8431 (1.8); 0.8327 (0.5); 0.8288 (0.6); 0.8207 (0.4); 0.1460 (0.5); 0.0080 (4.0); −0.0002 (117.1); −0.0085 (4.0); −0.1495 (0.5) I-207 [00351] 1H-NMR(400.2 MHz, d6-DMSO): δ = 9.3277 (2.3); 9.3108 (2.4); 8.1429 (2.0); 8.1083 (13.4); 8.0560 (2.1); 8.0514 (4.7); 8.0475 (6.2); 8.0395 (16.0); 8.0353 (8.0); 6.0074 (0.3); 5.9904 (1.6); 5.9732 (2.6); 5.9559 (1.7); 5.9389 (0.3); 3.3557 (33.4); 3.0237 (1.9); 2.6775 (0.8); 2.6729 (1.1); 2.6684 (0.8); 2.6642 (0.4); 2.5264 (3.7); 2.5216 (5.8); 2.5130 (65.4); 2.5085 (129.6); 2.5040 (167.5); 2.4994 (120.4); 2.4949 (57.8); 2.3397 (0.4); 2.3352 (0.8); 2.3308 (1.1); 2.3262 (0.8); 2.3218 (0.4); 2.0873 (0.5); 2.0757 (1.6); 2.0666 (1.1); 2.0637 (0.9); 2.0546 (2.1); 2.0425 (1.2); 2.0339 (1.1); 2.0217 (0.6); 1.5812 (8.7); 1.5637 (8.7); 1.0129 (2.9); 1.0078 (3.7); 0.9921 (2.8); 0.9870 (3.8); 0.9694 (0.4); 0.8937 (0.5); 0.8850 (0.5); 0.8815 (0.5); 0.8701 (2.2); 0.8642 (1.2); 0.8579 (2.4); 0.8524 (1.9); 0.8460 (1.9); 0.8413 (1.2); 0.8339 (1.7); 0.8223 (0.4); 0.8181 (0.6); 569.0 0.8104 (0.4); 0.1459 (0.3); 0.0079 (3.0); −0.0002 (85.3); −0.0086 (2.7); −0.1496 (0.4) I-208 [00352] 1H-NMR(400.2 MHz, d6-DMSO): δ = 9.3917 (4.9); 9.3750 (5.0); 8.3643 (9.3); 8.3612 (8.6); 8.3327 (9.8); 8.2823 (10.6); 8.1114 (16.0); 6.0320 (0.7); 6.0152 (2.9); 5.9981 (4.4); 5.9809 (2.9); 5.9632 (0.7); 3.3302 (60.7); 3.2496 (4.6); 3.1440 (0.8); 3.0232 (4.6); 2.6719 (1.4); 2.5030 (205.9); 2.3300 (1.2); 2.0872 (0.8); 2.0759 (1.7); 2.0653 (2.2); 2.0553 (3.5); 2.0436 (2.4); 2.0348 (1.9); 2.0225 (0.9); 1.5922 (15.9); 1.5749 (15.8); 1.1213 (0.4); 1.1051 (0.3); 1.0405 (0.4); 1.0290 (0.8); 1.0086 (7.8); 0.9878 (7.4); 0.9724 (1.1); 0.9598 (0.6); 0.8949 (0.9); 0.8580 (6.3); 0.8172 (0.7); −0.0004 (49.0) 516.0 .sup.1)‘abs’ denotes that the compound was obtained in an enantiomerically enriched or pure form with the major stereoisomer having the absolute configuration depicted in the drawing. .sup.2)‘lowT’ denotes that the measurement was conducted at a temperature of 260 Kelvin. .sup.3)The stated mass corresponds to the peak from the isotope pattern of the [M + H].sup.+ ion with the highest intensity. # denotes that the [M − H].sup.− ion was recorded.

TABLE-US-00002 TABLE 2 (Intermediates) ESI Mass Example Structure.sup.1) NMR Peak List.sup.2) (m/z).sup.3) INT-1 [00353] .sup.1H-N MR (400.2 MHz, d.sub.6-DMSO): δ = 8.9029 (3.3); 8.7163 (8.7); 8.5012 (7.7); 5.3372 (0.9); 5.3215 (0.9); 3.5684 (16.0); 3.3923 (1.8); 2.5270 (0.5); 2.5132 (10.4); 2.5092 (20.0); 2.5047 (26.0); 2.5003 (19.4); 1.6466 (7.8); 1.6296 (7.8); 0.0075 (0.8); −0.0002 (16.4); −0.0084 (0.7). 220.9 ([amine + H].sup.+) INT-2 [00354] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 8.7878 (2.3); 8.6835 (7.1); 5.3082 (0.4); 5.2912 (1.1); 5.2743 (1.1); 5.2577 (0.3); 3.5681 (2.4); 3.3381 (19.0); 2.6722 (0.3); 2.5255 (1.2); 2.5120 (21.3); 2.5077 (42.0); 2.5032 (54.6); 2.4986 (40.2); 2.4942 (20.0); 2.4237 (16.0); 2.4089 (0.5); 2.3300 (0.4); 1.6192 (6.0); 1.6022 (5.9); 1.1928 (0.6); 0.0080 (1.0); −0.0002 (26.0); −0.0085 (1.0). 235.2 ([amine + H].sup.+) INT-3 [00355] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 8.7134 (2.8); 8.3232 (0.4); 8.2848 (1.3); 8.2291 (0.4); 7.1668 (0.4); 5.3306 (0.8); 5.3158 (0.9); 4.6228 (1.5); 4.1433 (0.4); 4.0527 (0.7); 3.5681 (4.9); 3.3422 (123.1); 3.2988 (1.5); 2.9762 (0.7); 2.7750 (0.5); 2.6765 (0.8); 2.6721 (1.1); 2.6676 (0.8); 2.5253 (3.4); 2.5116 (71.0); 2.5075 (137.3); 2.5030 (180.1); 2.4985 (137.3); 2.4946 (70.8); 2.4216 (16.0); 2.4163 (6.9); 2.3345 (1.0); 2.3299 (1.2); 2.3254 (0.9); 2.3131 (0.6); 2.3064 (0.3); 1.6285 (6.8); 1.6116 (6.9); −0.0001 (0.6). 306.1 ([amine + H].sup.+) INT-4 [00356] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 8.6467 (2.4); 8.3215 (0.4); 8.1616 (6.6); 5.3460 (0.4); 5.3292 (1.2); 5.3121 (1.2); 5.2951 (0.4); 3.3375 (164.0); 3.2656 (1.7); 3.0291 (1.6); 2.7652 (0.6); 2.6764 (1.0); 2.6719 (1.4); 2.6674 (1.0); 2.5253 (4.7); 2.5117 (85.0); 2.5074 (166.5); 2.5029 (219.1); 2.4983 (165.2); 2.4940 (82.7); 2.4150 (16.0); 2.3343 (1.0); 2.3297 (1.4); 2.3252 (1.0); 2.3048 (0.5); 1.6210 (5.9); 1.6040 (5.8); −0.0001 (0.8) 281.1 ([amine+H].sup.+) INT-5 [00357] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 8.6668 (2.5); 8.4540 (7.2); 5.3471 (0.4); 5.3301 (1.4); 5.3131 (1.4); 5.2961 (0.4); 3.8887 (15.9); 3.5681 (0.9); 3.3315 (108.4); 2.6760 (0.7); 2.6715 (1.0); 2.6669 (0.7); 2.6624 (0.4); 2.5250 (3.2); 2.5201 (5.2); 2.5114 (58.1); 2.5071 (114.9); 2.5025 (149.8); 2.4979 (110.0); 2.4935 (54.0); 2.4232 (16.0); 2.3339 (0.7); 2.3293 (1.0); 2.3248 (0.7); 1.6174 (5.9); 1.6005 (5.8); 0.1459 (0.7); 0.0080 (6.6); −0.0002 (171.4); −0.0085 (6.6); −0.1496 (0.7). 267.9 ([amine + H].sup.+) INT-6 [00358] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ = 14.00 (br s, 1H, COOH), 8.42 (s, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 3.39 (s, 3H). 285.0 INT-7 [00359] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 8.85 (bs, 2H, NH.sub.2), 8.67 (s, 1H), 5.28-5.23 (m, 1H), 2.18-2.12 (m, 1H), 1.61 (d, 3H), 1.12-1.07 (m, 2H), .096-0.93 (m, 2H). 261.1 ([amine + H].sup.+) INT-8 [00360] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ = 14.0 (br s, 1H), 8.54 (s, 1H), 8.41 (s, 1H), 8.33 (s, 1H), 7.27 (t, J = 55 Hz, 1H). (Signal of CH.sub.3-group is hidden under solvent signal) 251.0 INT-9 [00361] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ = 13.9 (br s, 1H), 8.26 (s, 1H), 7.97 (s, 2H), 7.49 (t, J = 73 Hz, 1H). (Signal of CH.sub.3-group is hidden under solvent signal) 267.0 INT-10 [00362] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ = 1.28 (m, 2H), 1.53 (m, 2H), 7.64 (s, 1H), 7.80 (s, 1H), 7.95 (s, 1H), 13.45 (s, 1H). Measured using a Bruker AVANCE DRX 500 MHz spectrometer. 256.9.sup.# INT-11 [00363] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ = 13.60 (br s, 1H), 8.14 (s, 1H), 8.02 (d, J = 2.4 Hz, 2H), 2.00 (t, J = 19.2 Hz, 3H). Measured on a Varian S 400 MHz NMR. 262.9.sup.# INT-12 [00364] .sup.1H NMR (DMSO-ds, 400 MHz): δ = 13.4 (br s, 1H), 7.94 (s, 1H), 7.83 (s, 1H), 7.77 (s, 1H), 3.22-3.12 (m, 1H), 2.20-1.90 (m, 2H). 278.9 INT-13 [00365] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ = 13.82 (br s, 1H), 8.22 (d, J = 1.6 Hz, 1H), 8.13-8.03 (m, 2H), 2.36- 2.28 (m, 1H), 1.21-1.03 (m, 2H), 0.88 (dt, J = 6.9, 4.7 Hz, 2H). Measured with a Varian Gemini 2000 NMR machine. 295.0 INT-14 [00366] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ = 13.9 (br s, 1H), 8.21 (s, 1H), 7.97 (s, 1H), 7.93 (s, 1H), 7.50 (t, J = 73 Hz, 1H), 3.10-3.00 (m, 1H), 1.21-1.07 (m, 4H). 293.0 INT-15 [00367] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ = 13.9 (br s, 1H), 8.49 (s, 1H), 8.42 (s, 1H), 8.33 (s, 1H), 7.28 (t, J = 55 Hz, 1H), 3.12-3.05 (m, 1H), 1.22-1.08 (m, 4H). 277.0 INT-16 [00368] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ = 14.03-13.98 (br s, 1H), 8.36 (s, 1H), 8.17 (s, 1H), 8.14 (s, 1H), 3.14-3.08 (m, 1H), 1.22-1.08 (m, 4H). 311.0 INT-17 [00369] .sup.1H NMR (DMSO-ds, 400 MHz): δ = 8.34 (s, 1H), 8.10 (s, 1H), 7.99 (s, 1H), 7.23 (bs, 1H), 3.48-3.40 (quart., 2H), 1.14-1.09 (t, 3H). 299.0 INT-18 [00370] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ = 14.05 (br s, 1H), 8.32 (s, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 3.71-3.62 (m, 1H), 1.20-1.17 (d, 6H). 313.0 INT-19 [00371] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 8.81 (bs, 2H, NH.sub.2), 8.44 (s, 1H), 8.19 (s, 1H), 5.38-5.36 (m, 1H), 3.72 (s, 3H), 3.03 (s, 3H), 1.65 (d, 3H). 267.1 ([amine + H].sup.+) INT-20 [00372] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 8.99-8.95 (q, 1H), 8.76 (bs, 2H, NH.sub.2), 8.44 (s, 1H), 8.37 (s, 1H), 5.35 (m = bs, 1H), 2.81 (d, 3H), 1.65 (d, 3H). 253.1 ([amine+H].sup.+) INT-21 [00373] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ = 13.68 (br s, 1H), 7.99-7.96 (m, 1H), 7.84-7.66 (m, 1H), 7.53-7.50 (m, 1H), 1.90-1.81 (m, 2H), 1.73-1.64 (m, 2H). 270.0 INT-22 [00374] .sup.1H-NMR (CDCl.sub.3): δ = 7.83 (m, 1H), 8.2 (m, 1H), 8.2 (m, 1H), 10.1 (br, 1H). INT-23 [00375] .sup.1H-NMR (CDCl.sub.3): δ = 7.8 (m, 1H), 8.2 (m, 2H), 10.5 (br, 1H). INT-24 [00376] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ = 8.19 (s, 1H), 8.03 (s, 1H), 7.83 (s, 1H), 1.75 (d, J = 20 Hz, 6H). 259.0.sup.# INT-25 [00377] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ = 13.8 (br s, 1H), 7.71 (s, 2H), 7.58 (s, 1H), 7.45 (t, J = 73 Hz, 1H). 271.0.sup.# INT-26 [00378] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ = 13.3 (br s, 1H), 7.83 (s, 1H), 7.71 (s, 1H), 7.50 (s, 1H), 2.15-2.05 (m, 1H), 1.98 (t, J = 18.8 Hz, 3H), 1.06-1.00 (m, 2H), 0.80-0.74 (m, 2H). 227.1 INT-27 [00379] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6807 (1.4); 9.6639 (1.4); 8.5366 (5.1); 8.4114 (7.7); 8.3428 (2.2); 6.1159 (1.0); 6.0987 (1.6); 6.0815 (1.0); 3.8819 (16.0); 3.3343 (19.5); 2.5288 (0.8); 2.5153 (13.4); 2.5109 (26.3); 2.5063 (33.7); 2.5017 (24.6); 2.4973 (12.0); 2.3417 (15.9); 1.9916 (0.4); 1.6451 (5.6); 1.6277 (5.5); 1.3973 (3.9); 0.0080 (1.4); −0.0002(39.5); −0.0085 (1.6) 508.3 INT-28 [00380] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5220 (1.3); 9.5053 (1.4); 8.4078 (7.5); 8.2362 (2.5); 8.1885 (2.4); 8.0953 (2.3); 6.0737 (1.0); 6.0565 (1.5); 6.0394 (1.0); 3.8804 (15.9); 3.3316 (94.6); 2.6770 (0.4); 2.6725 (0.5); 2.6679 (0.4); 2.5498 (0.3); 2.5259 (1.7); 2.5211 (2.7); 2.5124 (33.2); 2.5080 (66.5); 2.5035 (86.0); 2.4989 (62.1); 2.4945 (30.1); 2.3377 (16.0); 1.6212 (5.5); 1.6038 (5.4); 0.0080 (1.4); −0.0002 (39.3); −0.0085 (1.3) 474.1 INT-29 [00381] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.6742 (1.4); 9.6574 (1.4); 8.5357 (5.0); 8.3427 (2.2); 8.2960 (7.6); 6.1147 (1.0); 6.0975 (1.6); 6.0803 (1.0); 4.0568 (0.4); 4.0390 (1.2); 4.0212 (1.2); 4.0034 (0.4); 3.3356 (3.6); 3.2797 (0.4); 2.6740 (0.4); 2.5274 (1.2); 2.5227 (1.9); 2.5140 (21.3); 2.5096 (42.5); 2.5050 (55.2); 2.5004 (40.4); 2.4959 (19.8); 2.3374 (16.0); 1.9907 (5.4); 1.9110 (4.3); 1.6426 (5.4); 1.6252 (5.4); 1.1942 (1.5); 1.1764 (3.0); 1.1702 (0.4); 1.1586 (1.5); 0.0080 (2.4); −0.0002 (64.9); −0.0085 (2.6) 494.1 INT-30 [00382] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5160 (1.4); 9.4991 (1.4); 8.2948 (7.5); 8.2372 (2.6); 8.1907 (2.6); 8.0942 (2.4); 6.0745 (1.0); 6.0575 (1.6); 6.0402 (1.0); 3.3321 (5.4); 2.6729 (0.4); 2.5264 (1.2); 2.5129 (24.4); 2.5085 (48.9); 2.5040 (63.3); 2.4994 (45.3); 2.4950 (21.7); 2.3346 (16.0); 1.9900 (0.8); 1.9102 (10.3); 1.6205 (5.6); 1.6031 (5.6); 1.3558 (0.5); 1.1759 (0.5); 1.0873 (0.3); 0.8716 (0.5); 0.8546 (1.8); 0.8382 (1.6); 0.8329 (1.0); 0.8235 (0.5); 0.8161 (0.4); 0.8073 (0.4) 460.0 INT-31 [00383] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 8.8211 (0.8); 8.4409 (2.8); 8.3543 (1.0); 3.5687 (16.0); 3.3897 (0.4); 3.3581 (19.1); 3.0301 (3.2); 2.5222 (0.4); 2.5136 (5.4); 2.5091 (11.1); 2.5045 (14.6); 2.4999 (10.4); 2.4953 (4.8); 1.6604 (2.3); 1.6435 (2.3); 0.9215 (0.6); 0.9098 (0.6); 0.9046 (0.5); 0.7672 (0.7); 0.7610 (0.7); 0.7583 (0.7); 0.7513 (0.5) 293.1 ([amine + H].sup.+) INT-32 [00384] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ = 8.75 (br, 3H), 8.45 (s, 1H), 5.3 (br, 1H), 3.9 (s, 3H), 2.1 (m, 1H), 1.6 (m, 3H), 1.1 (m, 2H), 0.9 (m, 2H). 294.2 ([amine + H].sup.+) INT-33 [00385] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ = 13.7 (br s, 1H), 7.94 (s, 1H), 7.80-7.40 (m, 4H). 269.0.sup.# INT-34 [00386] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.2351 (1.3); 9.2183 (1.4); 8.3803 (8.0); 7.5348 (3.0); 7.5313 (2.1); 7.5206 (1.7); 7.5179 (1.9); 7.2919 (1.9); 6.0004 (1.0); 5.9832 (1.6); 5.9660 (1.0); 3.8774 (16.0); 3.3249 (66.9); 2.6765 (0.4); 2.6718 (0.6); 2.6673 (0.4); 2.5253 (2.0); 2.5206 (3.1); 2.5119 (34.9); 2.5074 (68.6); 2.5028 (89.0); 2.4982 (64.6); 2.4937 (31.0); 2.3343 (0.4); 2.3297 (0.5); 2.3251 (0.4); 2.0842 (0.4); 2.0798 (0.7); 2.0712 (1.2); 2.0630 (0.9); 2.0590 (1.7); 2.0506 (1.6); 2.0383 (1.3); 2.0299 (0.7); 1.5901 (5.4); 1.5725 (5.4); 1.0571 (0.6); 1.0462 (2.0); 1.0406 (2.2); 1.0296 (1.2); 1.0252 (3.1); 1.0199 (3.3); 1.0007 (1.6); 0.9955 (2.2); 0.9009 (0.3); 0.8930 (0.4); 0.8887 (0.3); 0.8762 (1.0); 0.8716 (0.8); 0.8642 (1.0); 0.8593 (0.8); 0.8509 (0.8); 0.8462 (1.0); 0.8389 (0.8); 0.8342 (0.9); 0.8159 (0.5); 0.8092 (1.0); 0.7990 (2.0); 0.7966 (1.8); 0.7935 (1.9); 0.7866 (2.0); 0.7821 (1.9); 0.7706 (0.7); 0.1459 (0.4); 0.0080 (3.7); 522.2 −0.0002 (103.0); −0.0085 (3.3); −0.1496 (0.4) INT-35 [00387] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.2340 (2.5); 9.2171 (2.6); 8.2702 (16.0); 7.5369 (5.4); 7.5333 (4.0); 7.5251 (3.3); 7.5224 (3.6); 7.5200 (3.2); 7.2913 (3.5); 6.0207 (0.4); 6.0036 (1.8); 5.9864 (2.8); 5.9691 (1.8); 5.9517 (0.4); 3.3424 (2.7); 2.5294 (0.9); 2.5247 (1.3); 2.5160 (19.5); 2.5115 (39.7); 2.5069 (52.2); 2.5023 (38.0); 2.4977 (18.6); 2.3337 (0.3); 2.0934 (0.5); 2.0858 (0.7); 2.0813 (1.2); 2.0730 (2.2); 2.0647 (1.6); 2.0607 (3.1); 2.0525 (3.0); 2.0487 (1.9); 2.0399 (2.5); 2.0317 (1.3); 2.0280 (0.8); 2.0192 (0.6); 1.9912 (1.1); 1.9128 (2.8); 1.5925 (9.6); 1.5750 (9.6); 1.3578 (0.5); 1.1776 (0.6); 1.1714 (0.6); 1.0593 (1.0); 1.0481 (3.7); 1.0426 (4.0); 1.0320 (1.8); 1.0272 (4.0); 1.0216 (5.5); 1.0172 (3.4); 1.0120 (4.7); 0.9963 (2.8); 0.9913 (3.9); 0.9716 (0.4); 0.9670 (0.4); 0.9637 (0.4); 0.9046 (0.4); 0.9008 (0.6); 0.8931 (0.7); 0.8887 (0.7); 0.8760 (1.8); 0.8718 (1.6); 0.8640 (1.9); 0.8594 (1.5); 0.8511 (1.5); 0.8463 (1.7); 0.8392 (1.6); 0.8341 508.3 (1.6); 0.8139 (1.9); 0.8036 (3.9); 0.8011 (3.4); 0.7981 (3.5); 0.7912 (3.7); 0.7867 (3.6); 0.7752 (1.3); 0.0080 (1.3); −0.0002 (41.6); −0.0086 (1.3) INT-36 [00388] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 0.7 (m, 2H), 1.0 (m, 2H),. 1.6 (m, 3H), 2.1 (m, 1H), 6.0 (m, 1H), 8.1 (m, 2H), 8.3 (s, 1H), 8.45 (m, 1H), 9.6 (m, 1H), 14.0 (br, 1H). (Signal of methylsulfonyl group is hidden under solvent signal.) 546.2 INT-37 [00389] .sup.1H-NMR (400 MHz, d.sub.6-DMSO): δ = 8.59 (s, 1H), 4.70 (q, 1H, J = 6.8 Hz), 3.97 (s, 3H), 1.39 (d, 3H, J = 6.8 Hz). 251.1 INT-38 [00390] .sup.1H-NMR (400 MHz, d.sub.6-DMSO): δ = 8.76 (bs, NH.sub.2), 8.15 (s, 1H), 5.29 (m, 1H), 3.26 (bs, 3H), 3.03 (bs, 3H), 2.16-2.10 (m, 1H), 1.61 (d, 3H), 1.10-1.05 (m, 2H), 0.96-0.92 (m, 2H). 307.1 ([amine + H].sup.+) .sup.1)‘abs’ or ‘S’ or denotes that the compound was obtained in an enantiomerically enriched or pure form with the major stereoisomer having the absolute configuration depicted in the drawing. .sup.2)‘lowT’ denotes that the measurement was conducted at a temperature of 260 Kelvin. .sup.3)The stated mass corresponds to the peak from the isotope pattern of the [M + H].sup.+ ion with the highest intensity. .sup.#denotes that the [M − H].sup.− ion was recorded.

Biological Examples

Rhipicephalus (Boophilus) Microplus—In-Vitro Contact Tests Larval Cattle Tick (Strain Parkhurst, Resistant Against Synthetic Pyrethroids)

[0920] 9 mg compound is solved in 1 mL acetone and diluted with acetone to the desired concentration. 250 μL of the test solution is filled in 25 mL glass test tubes and homogeneously distributed on the inner walls by rotation and tilting on a shaking device (2 h at 30 rpm). With a compound concentration of 900 ppm, an inner surface of 44.7 cm.sup.2 and a homogeneous distribution, a dose of 5 μg/cm.sup.2 is achieved.

[0921] After the solvent has evaporated, each test tube is filled with 20-50 cattle tick larvae (Rhipicephalus microplus), closed with a perforated lid and incubated in a horizontal position at 85% relative humidity and 27° C. in an incubator. After 48 hours efficacy is determined. The larvae are patted on the ground of the tubes and negative geotactic behavior is recorded. Larvae that climb back to the top of the vial in a manner comparable to untreated control larvae are marked as alive, larvae not climbing back up comparable to untreated control larvae but are moving uncoordinatedly or only twitching their legs are marked as moribund, tick larvae remaining on the bottom and not moving at all are counted as dead.

[0922] A compound shows a good efficacy against Rhipicephalus microplus, if at a compound concentration of 5 μg/cm.sup.2 an efficacy of at least 80% is monitored. An efficacy of 100% means all larvae are dead or moribund; 0% means no larvae are dead or moribund.

[0923] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-16, I-17, I-18, I-19, I-20, I-21, I-23, I-24, I-25, I-26, I-28, I-30, I-31, I-35, I-38, I-64, I-66, I-67, I-71, I-72, I-73, I-76, I-77, I-80, I-81, I-89, I-91, I-94, I-97, I-98, I-102, I-108, I-124, I-125, I-126.

[0924] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): I-15, I-29, I-32, I-33, I-34, I-36, I-39, I-47, I-75, I-82.

[0925] In this test, for example, the following compounds from the preparation examples showed good activity of 80% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): I-69, I-84.

[0926] In this test, for example, the following compounds from the preparation examples showed good activity of 70% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): I-70.

Rhipicephalus (Boophilus) Microplus—Dip Test

[0927] Test animal: cattle ticks (Rhipicephalus microplus) strain Parkhurst, SP-resistant

[0928] Solvent: dimethyl sulfoxide

[0929] To produce a suitable preparation of active compound, 10 mg of active compound are dissolved in 0.5 mL solvent, and the concentrate is diluted with water to the desired concentration.

[0930] This compound solution is pipetted into tubes. 8-10 engorged, adult, female cattle ticks (Rhipicephalus microplus) are placed in perforated tubes. These tubes are immersed in the aqueous compound solution until the ticks are completely moistened. After the liquid has drained off, the ticks are transferred to a filter paper in a plastic tray and stored in a climate chamber.

[0931] After 7 days egg deposition of fertile eggs is monitored. Eggs where fertility is not visible are stored in a climate chamber till hatching after about 42 days. An efficacy of 100% means all eggs are infertile; 0% means all eggs are fertile.

[0932] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 100 ppm: I-1, I-2, I-5, I-6, I-9, I-14.

Rhipicephalus (Boophilus) Microplus—Injection Test

[0933] Solvent: dimethyl sulfoxide

[0934] To produce a suitable preparation of active compound, 10 mg of active compound are dissolved in 0.5 mL solvent, and the concentrate is diluted with solvent to the desired concentration.

[0935] Five adult engorged female ticks (Rhipicephalus microplus) are injected with 1 μL compound solution into the abdomen. The ticks are transferred into replica plates and incubated in a climate chamber.

[0936] After 7 days egg deposition of fertile eggs is monitored. Eggs where fertility is not visible are stored in a climate chamber till hatching after about 42 days. An efficacy of 100% means all eggs are infertile; 0% means all eggs are fertile.

[0937] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 20 μg/animal: I-1, I-2, I-36.

[0938] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 4 μg/animal: I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-23, I-24, I-25, I-26, I-27, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-39, I-66, I-67, I-69, I-82, I-83, I-84.

Ctenocephalides felis—In-Vitro Contact Tests Adult Cat Flea

[0939] 9 mg compound is solved in 1 mL acetone and diluted with acetone to the desired concentration. 250 μL of the test solution is filled in 25 mL glass test tubes and homogeneously distributed on the inner walls by rotation and tilting on a shaking device (2 h at 30 rpm). With a compound concentration of 900 ppm, an inner surface of 44.7 cm.sup.2 and a homogeneous distribution, a dose of 5 μg/cm.sup.2 is achieved.

[0940] After the solvent has evaporated, each test tube is filled with 5-10 adult cat fleas (Ctenocephalides felis), closed with a perforated lid and incubated in a lying position at room temperature and relative humidity. After 48 hours efficacy is determined. The fleas are patted on the ground of the tubes and are incubated on a heating plate at 45-50° C. for at most 5 minutes. Immotile or uncoordinated moving fleas, which are not able to escape the heat by climbing upwards, are marked as dead or moribund.

[0941] A compound shows a good efficacy against Ctenocephalides felis, if at a compound concentration of 5 μg/cm.sup.2 an efficacy of at least 80% is monitored. An efficacy of 100% means all fleas are dead or moribund; 0% means no fleas are dead or moribund.

[0942] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): I-1, I-4, I-5, I-6, I-9, I-15, I-21, I-23, I-24, I-25, 1-26, I-28, I-36, I-64, I-65, I-70, I-71, I-89, I-94, I-97, I-98, I-102, I-108, I-124, I-125.

[0943] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): I-10, I-38, I-69, I-75.

[0944] In this test, for example, the following compounds from the preparation examples showed good activity of 80% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): I-2, I-17, I-33, I-37, I-39, I-72, I-76, I-82, I-83, I-126.

Ctenocephalides felis—Oral Test

[0945] Solvent: dimethyl sulfoxide

[0946] To produce a suitable preparation of active compound, 10 mg of active compound are dissolved in 0.5 mL solvent, and the concentrate is diluted with cattle blood to the desired concentration.

[0947] Approximately 20 adult unfed cat fleas (Ctenocephalides felis) are placed in flea chambers. The blood chamber, sealed with parafilm on the bottom, are filled with cattle blood supplied with compound solution and placed on the gauze covered top of the flea chamber, so that the fleas are able to suck the blood. The blood chamber is heated to 37° C. whereas the flea chamber is kept at room temperature.

[0948] After 2 days mortality in % is determined. 100% means all the fleas have been killed; 0% means none of the fleas have been killed.

[0949] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 100 ppm: I-1, I-2, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-24, I-25, I-26, I-27, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-39, 1-82, I-83, I-84.

[0950] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 100 ppm: I-23.

[0951] In this test, for example, the following compounds from the preparation examples showed good activity of 80% at an application rate of 100 ppm: I-3.

Rhipicephalus sanguineus—In-Vitro Contact Tests with Adult Brown Dog Ticks

[0952] 9 mg compound is solved in 1 mL acetone and diluted with acetone to the desired concentration. 250 μL of the test solution is filled in 25 mL glass test tubes and homogeneously distributed on the inner walls by rotation and tilting on a shaking device (2 h at 30 rpm). With a compound concentration of 900 ppm, an inner surface of 44.7 cm.sup.2 and a homogeneous distribution, a dose of 5 μg/cm.sup.2 is achieved.

[0953] After the solvent has evaporated, each test tube is filled with 5-10 adult brown dog ticks (Rhipicephalus sanguineus), closed with a perforated lid and incubated in a lying position at room temperature and relative humidity. After 48 hours efficacy is determined. The ticks are patted on the ground of the tubes and are incubated on a heating plate at 45-50° C. for at most 5 minutes. Immotile or uncoordinated moving ticks, which are not able to escape the heat by climbing upwards, are marked as dead or moribund.

[0954] A compound shows a good efficacy against Rhipicephalus sanguineus, if at a compound concentration of 5 μg/cm.sup.2 an efficacy of at least 80% is monitored. An efficacy of 100% means all ticks are dead or moribund; 0% means no ticks are dead or moribund.

[0955] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, 1-12, I-13, I-14, I-15, I-17, I-18, I-20, I-21, I-23, I-25, I-30, I-31, I-64, I-72, I-91, I-94, I-97, I-98.

[0956] In this test, for example, the following compounds from the preparation examples showed good activity of 80% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): I-1, I-19, I-24, I-38, I-69, I-89, I-125.

Diabrotica Balteata—Spray Test

[0957] Solvent: 78.0 parts by weight of acetone [0958] 1.5 parts by weight of dimethylformamide [0959] Emulsifier: alkylarylpolyglycol ether

[0960] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvent, and the concentrate is diluted with water, containing an emulsifier concentration of 1000 ppm, to the desired concentration. Further test concentrations are prepared by dilution with emulsifier containing water.

[0961] Soaked wheat seeds (Triticum aestivum) are placed in a multiple well plate filled with agar and some water and are incubated for 1 day to germinate (5 seeds per well). The germinated wheat seeds are sprayed with a test solution containing the desired concentration of the active ingredient. Afterwards each unit is infected with 10-20 larvae of the banded cucumber beetle (Diabrotica balteata).

[0962] After 7 days efficacy in % is determined. 100% means all the seedlings have grown up like in the untreated, uninfected control; 0% means none of the seedlings have grown.

[0963] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 100 g/ha (=32 μg/well): I-2, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-26, I-27, I-28, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-52, I-53, I-55, I-56, I-58, I-59, I-60, I-61, I-62, I-63, I-64, I-65, I-66, I-67, I-68, I-69, I-71, I-72, I-75, I-77, I-80, I-81, I-84, I-85, I-86, I-87, I-88, I-89, I-90, I-91, I-92, I-95, I-99, I-100, I-101, I-102, I-103, I-104, I-105, I-106, I-107, I-108, I-109, I-110, I-111, I-112, I-113, I-114, I-115, I-116, I-118, I-119, I-121, I-122, I-123, I-124, I-125, I-126, I-128, I-129, I-130, I-131, I-132, I-133, I-134, I-135, I-136, I-137, I-138, I-139, I-140, I-142, I-144, I-145, I-146, I-147, I-148, I-149, I-150, I-151, I-152, I-153, I-154, I-155, I-156, I-157, I-158, I-159, I-160, I-161, I-162, I-163, I-164, I-165, I-166, I-167, I-168, I-169, I-170, I-171, I-173, I-200.

[0964] In this test, for example, the following compounds from the preparation examples showed good activity of 80% at an application rate of 100 g/ha (=32 μg/well): I-1, I-40, I-57, I-82, I-143.

Myzus persicae—oral test [0965] Solvent: 100 parts by weight acetone

[0966] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvent, and the concentrate is diluted with water to the desired concentration. 50 μL compound solution is filled in microtiter plates and 150 μL IPL41 insect medium (33%+15% sugar) is added to obtain a total volume of 200 μL per well. Afterwards the plates are sealed with parafilm through which a mixed population of the green peach aphid (Myzus persicae) can suck on the compound preparation.

[0967] After 5 days mortality in % is determined. 100% means all aphids have been killed and 0% means none of the aphids have been killed.

[0968] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 4 ppm: I-2, I-4, I-5, I-6, I-7, I-8, I-9, I-11, I-14, I-17, I-18, I-21, I-23, I-24, I-25, I-26, I-30, I-31, I-33, I-34, I-35, I-36, I-37, I-39, I-42, I-66, I-67, I-69, I-72, I-73, I-74, I-75, I-78, 1-79, I-81, I-82, I-83, I-84.

[0969] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 4 ppm: I-1, I-3, I-40.

Myzus persicae—Spray Test [0970] Solvent: 78.0 parts by weight acetone [0971] 1.5 parts by weight dimethylformamide [0972] Emulsifier: alkylarylpolyglycol ether

[0973] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvents and is diluted with water, containing an emulsifier concentration of 1000 ppm, to the desired concentration. Further test concentrations are prepared by dilution with emulsifier containing water.

[0974] Chinese cabbage (Brassica pekinensis) leaf disks infected with all instars of the green peach aphid (Myzus persicae), are sprayed with a preparation of the active ingredient of the desired concentration.

[0975] After 5 days mortality in % is determined. 100% means all aphids have been killed and 0% means none of the aphids have been killed.

[0976] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 100 g/ha: I-6, I-9, I-18, I-21, I-24, I-52, I-64, I-65, I-85, I-86, I-87, I-89, I-95, I-99, I-112, I-113, I-129, I-161, I-171.

[0977] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 100 g/ha: I-4, I-5, I-23, I-31, I-35, I-46, I-47, I-50, I-51, I-66, I-69, I-73, I-74, I-90, I-91, I-100, I-102, I-114, I-119, I-120, I-125, I-128, I-130, I-137, I-142, I-148, I-152, I-154, I-155.

Nezara viridula—Spray Test [0978] Solvent: 78.0 parts by weight of acetone [0979] 1.5 parts by weight of dimethylformamide [0980] Emulsifier: alkylarylpolyglycol ether

[0981] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvent, and the concentrate is diluted with water, containing an emulsifier concentration of 1000 ppm, to the desired concentration. Further test concentrations are prepared by dilution with emulsifier containing water.

[0982] Barley plants (Hordeum vulgare) are sprayed with a test solution containing the desired concentration of the active ingredient and are infested with larvae of the southern green stink bug (Nezara viridula).

[0983] After 4 days mortality in % is determined. 100% means all the stink bugs have been killed; 0% means none of the stink bugs have been killed.

[0984] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 500 g/ha: I-46, I-50, I-51, I-52, I-54, I-60, I-64, I-65, I-89, I-91, I-99, I-100, I-102, I-105, I-106, I-107, I-108, I-109, I-110, I-111, I-112, I-113, I-114, I-117, I-118, I-119, I-120, I-121, I-123, I-124, I-125, I-128, I-130, I-131, I-134, I-136, I-137, I-142, I-165, I-166, I-167, I-168, I-169, 1-170, I-171, I-173, I-174, I-175.

[0985] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 500 g/ha: I-103, I-104, I-115, I-158.

[0986] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 100 g/ha: I-21, I-51, I-65, I-84, I-99, I-100, I-105, I-109, I-112, I-113, I-114, I-117, I-118, I-119, I-120, I-124, I-136.

[0987] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 100 g/ha: I-9, I-50, I-82, I-107, I-110, I-128.

Nilaparvata lugens—Spray Test [0988] Solvent: 78.0 parts by weight of acetone [0989] 1.5 parts by weight of dimethylformamide [0990] Emulsifier: alkylarylpolyglycol ether

[0991] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvents and is diluted with water, containing an emulsifier concentration of 1000 ppm, to the desired concentration. Further test concentrations are prepared by dilution with emulsifier containing water.

[0992] Rice plants (Oryza sativa) are sprayed with a preparation of the active ingredient of the desired concentration and the plants are infested with the brown planthopper (Nilaparvata lugens).

[0993] After 4 days mortality in % is determined. 100% means all planthoppers have been killed and 0% means none of the planthoppers have been killed.

[0994] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 500 g/ha: I-89, I-91, I-102, I-113, I-119, I-120, I-128, I-129, I-138, I-165.

[0995] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 500 g/ha: I-64, I-65.

[0996] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 100 g/ha: I-5, I-6, I-9.

[0997] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 100 g/ha: I-4, I-10, I-64.

Spodoptera frugiperda—Spray Test [0998] Solvent: 78.0 parts by weight acetone [0999] 1.5 parts by weight dimethylformamide [1000] Emulsifier: alkylarylpolyglycol ether

[1001] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvents and is diluted with water, containing an emulsifier concentration of 1000 ppm, to the desired concentration. Further test concentrations are prepared by dilution with emulsifier containing water.

[1002] Maize (Zea mays) leaf sections are sprayed with a preparation of the active ingredient of the desired concentration. Once dry, the leaf sections are infested with fall armyworm larvae (Spodoptera frugiperda).

[1003] After 7 days mortality in % is determined. 100% means all caterpillars have been killed and 0% means none of the caterpillars have been killed.

[1004] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 100 g/ha: I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-14, I-16, I-17, I-18, I-19, I-21, I-22, I-24, I-25, I-26, I-28, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52, I-53, I-54, I-55, I-56, I-57, I-59, I-60, I-61, I-62, I-64, I-65, I-66, I-67, I-68, I-69, I-72, I-76, I-77, I-80, I-81, I-82, I-85, I-86, I-87, I-88, I-89, I-90, I-91, I-92, I-95, I-99, I-100, I-101, I-102, I-103, I-104, I-105, I-106, I-107, I-108, I-109, I-110, I-111, I-112, I-114, I-115, I-116, I-118, I-119, I-120, I-122, I-123, I-124, I-125, I-126, I-128, I-129, I-130, I-131, I-132, I-133, I-134, I-135, I-136, I-137, I-138, I-139, I-140, I-141, I-142, I-143, I-144, I-145, I-146, I-147, I-148, I-149, I-150, I-151, I-152, I-153, I-154, I-155, I-156, I-157, I-158, I-159, I-160, I-161, I-162, I-163, 1-164, I-165, I-166, I-168, I-169, I-170, I-171.

[1005] In this test, for example, the following compounds from the preparation examples showed good activity of 83% at an application rate of 100 g/ha: I-13, I-15, I-23.

Spodoptera frugiperda—spray test [1006] Solvent: 14 parts by weight of dimethylformamide [1007] Emulsifier: alkylaryl polyglycol ether

[1008] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvent and is diluted with water, containing an emulsifier concentration of 1000 ppm, to the desired concentration. Further test concentrations are prepared by dilution with emulsifier containing water. Ammonium salt and/or penetration enhancer in a dosage of 1000 ppm are added to the desired concentration if necessary.

[1009] Cotton leaves (Gossypium hirsutum) are treated by being sprayed with the preparation of the active compound of the desired concentration and are infested with caterpillars of the fall army worm (Spodoptera frugiperda).

[1010] After 7 days mortality in % is determined. 100% means all the caterpillars have been killed and 0% means none of the caterpillars have been killed.

[1011] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 20 ppm: I-93, I-94, I-96, I-97, I-98.

[1012] Aedes aegypti test (AEDSAE surface treatment & contact assay) [1013] Solvent: Aceton+2000 ppm rapeseed oil methyl ester (RME)

[1014] In order to produce a sufficient, active ingredient containing solution it is necessary to solve the test compound in the solvent-mix (acetone at 2 mg/ml/RME 2000 ppm). This solution is pipetted onto a glazed tile and after evaporation of the acetone, adult mosquitoes of the species Aedes aegypti strain MONHEIM are placed onto the dried surface. The exposure time is 30 minutes.

[1015] Mortality in percent (%) is determined 24 hours after contact of the insects to the treated surface. 100% mortality means that all tested insects are dead, whereas 0% means that no insect died.

[1016] The following examples showed in this test efficacy of 80-100% at a surface concentration of 20 mg/m.sup.2: I-2, I-4, I-9, I-14, I-18, I-21, I-26, I-31, I-33, I-36, I-39, I-47, I-52, I-64, I-85, I-87, I-89, I-91, I-99, I-118, I-130, I-142.

[1017] The following examples showed in this test efficacy of 80-100% at a surface concentration of 4 mg/m.sup.2: I-1, I-2, I-6, I-9, I-18, I-21, I-31, I-33, I-36, I-47, I-85, I-87, I-90, I-99, I-105, I-142.

Culex quinquefasciatus Test (CULXFA Surface Treatment & Contact Assay) [1018] Solvent: Aceton+2000 ppm rapeseed oil methyl ester (RME)

[1019] In order to produce a sufficient, active ingredient containing solution it is necessary to solve the test compound in the solvent-mix (acetone at 2 mg/ml/RME 2 OOOppm). This solution is pipetted onto a glazed tile and after evaporation of the acetone, adult mosquitoes of the species Culex quinquefasciatus strain P00 are placed onto the dried surface. The exposure time is 30 minutes.

[1020] Mortality in percent (%) is determined 24 hours after contact of the insects to the treated surface. 100% mortality means that all tested insects are dead, whereas 0% means that no insect died.

[1021] The following examples showed in this test efficacy of 80-100% at a surface concentration of 4 mg/m.sup.2: I-1, I-2.

Anopheles funestus Test (ANPHFU Surface Treatment & Contact Assay) [1022] Solvent: Aceton+2000 ppm rapeseed oil methyl ester (RME)

[1023] In order to produce a sufficient, active ingredient containing solution it is necessary to solve the test compound in the solvent-mix (acetone at 2 mg/ml/RME 2000 ppm). This solution is pipetted onto a glazed tile and after evaporation of the acetone, adult mosquitoes of the species Anopheles funestus strain FUMOZ-R (Hunt et al., Med. Vet. Entomol. 2005 September; 19(3): 271-275) are placed onto the dried surface. The exposure time is 30 minutes.

[1024] Mortality in percent (%) is determined 24 hours after contact of the insects to the treated surface. 100% mortality means that all tested insects are dead, whereas 0% means that no insect died.

[1025] The following examples showed in this test efficacy of 80-100% at a surface concentration of 20 mg/m.sup.2: I-26, I-64, I-85, I-87, I-118, I-130, I-142.

[1026] The following examples showed in this test efficacy of 80-100% at a surface concentration of 4 mg/m.sup.2: I-1, I-2, I-31, I-36, I-85, I-118.

Musca domestica Test (MUSCDO Surface Treatment & Contact Assay) [1027] Solvent: Aceton+2000 ppm rapeseed oil methyl ester (RME)

[1028] In order to produce a sufficient, active ingredient containing solution it is necessary to solve the test compound in the solvent-mix (acetone at 2 mg/ml/RME 2000 ppm). This solution is pipetted onto a glazed tile and after evaporation of the acetone, adult flies of the species Musca domestica strain WHO-N are placed onto the dried surface. The exposure time is 30 minutes.

[1029] Mortality in percent (%) is determined 24 hours after contact of the insects to the treated surface. 100% mortality means that all tested insects are dead, whereas 0% means that no insect died.

[1030] The following examples showed in this test efficacy of 80-100% at a surface concentration of 20 mg/m.sup.2: I-1, I-2, I-4, I-6, I-9, I-14, I-18, I-21, I-26, I-31, I-33, I-39, I-47, I-52, I-59, I-64, I-85, I-87, I-89, I-90, I-91, I-99, I-103, I-118, I-130, I-142.

[1031] The following examples showed in this test efficacy of 90-100% at a surface concentration of 4 mg/m.sup.2: I-1, I-2, I-5, I-6, I-14, I-18, I-21, I-26, I-31, I-39, I-47, I-52, I-64, I-85, I-87, I-90, I-91, I-99, I-130, I-142.

Comparison Examples

[1032] Plutella xylostella—spray test (PLUTMA) [1033] Solvent: 14 parts by weight of dimethylformamide [1034] Emulsifier: alkylaryl polyglycol ether

[1035] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvent and is diluted with water, containing an emulsifier concentration of 1000 ppm, to the desired concentration. Further test concentrations are prepared by dilution with emulsifier containing water. Ammonium salt and/or penetration enhancer in a dosage of 1000 ppm are added to the desired concentration if necessary.

[1036] Cabbage leaves (Brassica oleracea) are treated by being sprayed with the preparation of the active compound of the desired concentration and are infested with larvae of the diamondback moth (Plutella xylostella).

[1037] After the specified period of time, mortality in % is determined. 100% means all the caterpillars have been killed and 0% means none of the caterpillars have been killed.

[1038] In this test, for example, the following compounds from the preparation examples show a superior level of activity compared to the prior state of the art: see table 3

Spodoptera fruaiperda—Spray Test (SPODFR) [1039] Solvent: 14 parts by weight of dimethylformamide [1040] Emulsifier: alkylaryl polyglycol ether

[1041] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvent and is diluted with water, containing an emulsifier concentration of 1000 ppm, to the desired concentration. Further test concentrations are prepared by dilution with emulsifier containing water. Ammonium salt and/or penetration enhancer in a dosage of 1000 ppm are added to the desired concentration if necessary.

[1042] Cotton leaves (Gossypium hirsutum) are treated by being sprayed with the preparation of the active compound of the desired concentration and are infested with caterpillars of the fall army worm (Spodoptera frugiperda).

[1043] After the specified period of time mortality in % is determined. 100% means all the caterpillars have been killed and 0% means none of the caterpillars have been killed.

[1044] In this test, for example, the following compounds from the preparation examples show a superior level of activity compared to the prior state of the art: see table 3

TABLE-US-00003 TABLE 3 Comparison examples (1) % Efficacy Substance Structure Object Concentration dat Ex.-No. I-085 Known from WO 2019206799 [00391] PLUTMA SPODFR 20 ppm  4 ppm  40 7 dat  20 7 dat Ex.-No. I-1 According to the invention [00392] PLUTMA SPODFR 20 ppm  4 ppm 100 7 dat 100 7 dat dat = days after treatment
Nezara viridula—Spray Test (NEZAVI) [1045] Solvent: 78.0 parts by weight of acetone [1046] 1.5 parts by weight of dimethylformamide [1047] Emulsifier: alkylarylpolyglycol ether

[1048] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvent, and the concentrate is diluted with water, containing an emulsifier concentration of 1000 ppm, to the desired concentration. Further test concentrations are prepared by dilution with emulsifier containing water.

[1049] Barley plants (Hordeum vulgare) are sprayed with a test solution containing the desired concentration of the active ingredient and are infested with larvae of the southern green stink bug (Nezara viridula).

[1050] After the specified period of time, mortality in % is determined in comparison to the untreated control plant. 100% means all the stink bugs have been killed; 0% means none of the stink bugs have been killed.

[1051] In this test, for example, the following compound from the preparation examples shows a superior level of activity compared to the prior state of the art: see list

Spodoptera fruaiperda—Spray Test (SPODFR) [1052] Solvent: 78.0 parts by weight acetone [1053] 1.5 parts by weight dimethylformamide [1054] Emulsifier: alkylarylpolyglycol ether

[1055] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvents and is diluted with water, containing an emulsifier concentration of 1000 ppm, to the desired concentration. Further test concentrations are prepared by dilution with emulsifier containing water.

[1056] Maize (Zea mays) leaf sections are sprayed with a preparation of the active ingredient of the desired concentration. Once dry, the leaf sections are infested with fall armyworm larvae (Spodoptera frugiperda).

[1057] After the specified period of time, mortality in % is determined in comparison to the untreated control plant. 100% means all caterpillars have been killed and 0% means none of the caterpillars have been killed.

[1058] In this test, for example, the following compound from the preparation examples shows a superior level of activity compared to the prior state of the art: see list

TABLE-US-00004 TABLE 4 comparison examples (2) % Efficacy Substance Structure Object Concentration dat Ex.-No. I-077 Known from WO 2019197468 [00393] NEZAVI SPODFR 500 g ai/ha 100 g ai/ha  20 g ai/ha  0 4 dat  67 7 dat  33 7 dat Ex.-No. I-60 According to the invention [00394] NEZAVI SPODFR 500 g ai/ha 100 g ai/ha  20 g ai/ha 100 4 dat 100 7 dat 100 7 dat Ex.-No. I-110 According to the invention [00395] NEZAVI SPODFR 500 g ai/ha 100 g ai/ha  20 g ai/ha 100 4 dat 100 7 dat  67 7dat dat = days after treatment